In Neuroscience: Neurodegeneration

May 2010 | Volume 4 | Issue 1
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IN NEUROSCIENCE
NEURODEgENERATION
Inflammation, Brain Circuitry, Hormones, Cell Therapy, Dementia, Parkinsons, ALS, Huntingtons, Alzheimers, Market & Funding Overview, Aging Society - Ethics & Challenges
Striatum and Decision, Multisensory Integration, Machine Learning and Neuroscience, Schizophrenic Mice, Brain Machine Dialog, Functional Oscillations, Information Theoretic Toolbox, Object Recognition, Auditory Drivers and Modulators
About Frontiers in neuroscience

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contemplating circumstances by Wendy J. st. christopher All rights reserved. www.art166.biz An artists impression on neurodegeneration: confusion, fuzzy thinking, and feeling trapped.
exploring the function of neural oscillations in early sensory systems Kilian Koepsell, Xin Wang, Judith A. Hirsch and Friedrich T. Sommer 62 open source tools for the information theoretic analysis of neural data Robin A. A. Ince, Alberto Mazzoni, Rasmus S. Petersen and Stefano Panzeri 71 invariance in visual object recognition requires training: a computational argument Robbe L. T. Goris and Hans P. Op de Beeck April 2010 | Volume 4 | Issue 1 79 Drivers and modulators in the central auditory pathways Charles C. Lee and S. Murray Sherman
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90 92 neurodegeneration: a growing global burden Gemma Casadesus and Mark A. Smith statins and dementia: the interface between brain health and neurovascular health Benjamin Wolozin brain food and vitamin D William B. Grant Models of thalamocortical circuitry to investigate neurodegeneration Damien Coyle, Liam P. Maguire and T. Martin McGinnity neurological and peripheral inflammation: the dark and light sides of a two-way system in neurodegeneration Andrea Malaspina and Egle Solito the new era of hormones in neurodegeneration Natalia Crespo-Biel, Hyunjin Kim, Mark A. Smith and Gemma Casadesus intracellular protein degradation and chronic neurodegenerative disease Lynn Bedford, Simon Paine, James Lowe and R. John Mayer restorative cell therapies in neurodegeneration Alberto Martnez-Serrano llluminating polyphenols in neurodegeneration Hayley C. Fivecoat and Giulio M. Pasinetti Abnormal mitochondrial dynamics and neurodegeneration Xiongwei Zhu cell to cell transmission of synucleinopathy: is it a key mechanism? Atsushi Takeda Dementia with Lewy bodies James F. Morley and John E. Duda Parkinsons disease: advances in molecular neuropathology Isidro Ferrer Amyotrophic lateral sclerosis Orla Hardiman current outlook on Huntingtons disease Mark E. Hester, Mathew J. Murtha and Brian K. Kaspar cholesterol and Alzheimers disease Othman Ghribi
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Alzheimers disease goes tau Khalid Iqbal secretases and Alzheimers disease Kumar Sambamurti Mitochondrial oxygen toxicity in Alzheimers disease Ana Lloret and Jose Via Animal models of Parkinsons disease Michael K. Lee common pathogenic mechanisms of Alzheimers disease and cancer Hyoung-gon Lee, Xiongwei Zhu, Hyun-Pil Lee, Xinglong Wang, Vladan Bajic, Gemma Casadesus and Mark A. Smith Postulates to help validate a causal relationship to Alzheimers disease Jack C. de la Torre new pills for Auguste D? Merc Boada WAnteD: a neuroprotective agent in Parkinsons disease D. James Surmeier and Tanya Simuni biomarkers of neurodegeneration that would please the vampire Judith A. Potashkin Drug discovery in neurodegeneration mind the gap Adrian J. Ivinson neurodegenerative disorders: gene therapy on clinical trial Patrick Aebischer research highlights Featured scientist serge Przedborski
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146 148 150 152 154 156 158 160 the burgeoning Alzheimers disease crisis William Thies A patient with Alzheimers disease Martin J. Sadowski Legal and ethical aspects of dementia Daniel Marson caregivers of adults with cognitive impairments: future challenges Kathleen Kelly Home caregivers: the hidden patients the cost of Alzheimers disease Dementia underestimated Dementia worldwide
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170 174 176 178 180 neurodegenerative market space improving the efficiency of cns drug discovery Katherine Tsaioun industry highlights on the horizon Global industry
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Frontiers in Neuroscience
May patient with Parkinsons disease. parkinsons disease. Fluorescent deconvolution micrograph of brain tissue of a2010 | Volume 4 | Issue 1 | 89
RESEARCH
NEURODEGENERATION
eurodegenerative diseases are perhaps one of the biggest legacies of modern medicine. While rapid advancements in disease treatment and technology afford us longer life expectancies, this consequently subjects us to a greater risk of age-related neuro-deterioration, such as that due to Alzheimers and Parkinsons disease. As such, the prevalence of neurodegenerative disease among the global population has risen exponentially over the last century and is expected to continue to do so. In fact, with no effective treatments for neurodegeneration, such exponential growth of disease poses a significant threat to our society both economic and social. Patient care, in particular, imposes a severe burden on our healthcare system, as well as on the friends and families of the patient. A network of institutions and caregivers is required to tend to the sick, and co-morbidity and other medical conditions associated with declining health worsen this burden. Clearly, in the 21st century, it is of critical importance that we not only expand our understanding of neuro-
degeneration, but then use this knowledge to affect preventative measures or therapeutic targets. Fortunately, the field of neuroscience is also growing exponentially, such that our knowledge of debilitating neurodegenerative diseases, such as Alzheimers disease, Huntingtons disease, Parkinsons disease, amyotrophic lateral sclerosis, multiple sclerosis, and fronto-temporal lobe dementia, has significantly improved over the past few decades, and, in some instances, has provided insight into potential avenues for disease-preventing therapies. Although there is much to be done, the improvements in the field are increasing at an ever-growing rate, and this issue of Frontiers in Neuroscience provides an exceptional conglomeration of recent reports on the subject from leaders in the field. These reports range from novel mechanistic pathways of neurodegeneration in disease to therapeutic implications for future investigations. As editors of Frontiers in Aging, we are grateful to the authors for their outstanding contributions. With such talented investigators at the helm, there is clearly much to be excited about in the field and a bright future ahead.
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NEURODEGENERATION: A GROWING GlObAl bURDEN

by Gemma Casadesus and Mark A. Smith
gemma casadesus received her Ph.D. in Physiological Psychology from Tufts University in 2003. Following a Post-doctoral Fellowship in the Department of Pathology at Case Western Reserve University, she was recruited as a faculty member and Director of the CWRU Rodent Behavior Core at the Department of Neurosciences in 2007. Her research focuses on the switch mechanisms that drive normal aging toward a pathogenic agerelated condition, such as Alzheimers disease (AD). Dr. Casadesus serves on various editorial boards and has authored over 70 peerreviewed manuscripts and chapters in the fields of aging and AD. gxc40@case.edu
Mark A. smith received his Ph.D. in Biochemistry from the University of Nottingham, UK, in 1990. Following a Research Fellowship at Sandoz Forschungsinstitut, Vienna, Austria, Dr. Smith joined CWRU in 1992 and is currently a Professor of Pathology. The focus of Dr. Smiths research involves investigating the pathological mechanism(s) underlying selective neuronal death in neurodegenerative and neurodevelopmental diseases. In addition to serving on numerous editorial and grant review boards, Dr. Smith has authored over 800 peer-reviewed manuscripts and chapters, and is recognized as one of the most highly published and cited researchers in the field of Alzheimers disease. mark.smith@case.edu
December 2009 | Volume 3 | Issue 3 | 91
STATINS AND DEMENTIA: ThE INTERFACE bETWEEN bRAIN hEAlTh AND NEUROVASCUlAR hEAlTh
by benjamin Wolozin
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benjamin Wolozin, M.D., Ph.D., is Professor of Pharmacology and Neurology at Boston University, School of Medicine. He earned his M.D./Ph.D. degrees from Albert Einstein College of Medicine in 1988. Dr. Wolozins research investigates the pathophysiology of neurodegenerative diseases. His research on the biology of neurodegenerative diseases (Alzheimers, Parkinsons, ALS) investigates the interaction between genetic factors implicated in these diseases and environmental factors. His epidemiological research program examines the effects of FDA-approved medications on the incidence and progression of dementia. bwolozin@bu.edu
RefeRences
Li, G., Larson, E. B., Sonnen, J. A., Shofer, J. B., Petrie, E. C., Schantz, A., Peskind, E. R., Raskind, M. A., Breitner, J. C., and Montine, T. J. (2007). Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 69, 878-885. Li, N., Lee, A., Whitmer, R., Kivipelto, M., Lawler, E., Kazis, L., and Wolozin, B. (in press). Use of Angiotensin Receptor Blockers and the Risk of Dementia in a Predominantly Male Population: A Prospective Cohort Analysis. Br. Med. J. Wolozin, B., Brown, J., 3rd, Theisler, C., and Silberman, S. (2004). The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimers disease. CNS Drug Rev. 10, 127-146. Wolozin, B., Manger, J., Bryant, R., Cordy, J., Green, R. C., and McKee, A. (2006). Re-assessing the relationship between cholesterol, statins and Alzheimers disease. Acta Neurol. Scand. Suppl. 185, 63-70. Wolozin, B., Wang, S. W., Li, N. C., Lee, A., Lee, T. A., and Kazis, L. E. (2007). Simvastatin is associated with a reduced incidence of dementia and Parkinsons disease. BMC Med. 5, 20.
Multiple studies have examined whether statins exhibit neuroprotective actions, but these studies have mostly focused on Alzheimers disease (AD) (Wolozin et al., 2004; Wolozin et al., 2006; Wolozin et al., 2007). The animal and epidemiological studies have been overwhelmingly positive, although the exact mechanism by which a neuroprotective action might occur remains controversial. The ability of statins to reduce cholesterol levels leads to pleiotropic effects on neurons, astrocytes, inflammatory cells and endothelial cells (Wolozin et al., 2006). Beyond 90% inhibition of HMG-CoA reductase, the levels of cholesterol precursors drop to a point where substrate levels for other enzymes in the cascade become rate limiting. The key substrates that attract focus are geranyl and farnesyl pyrophosphate, which are required for activation of small GTPases, such as ras, rac, rho and CDC42, and are required for the inflammatory response (Wolozin et al., 2006). Studies in animal models and the human brain support a putative inhibitory role of statins on the inflammatory cascade. Humans taking statins show reduced microglial activation and reduced tangle pathology (Wolozin et al., 2006). These results are also observed in transgenic models of AD (Li et al.,
2007). Thus, statin-mediated dampening of the inflammatory response is thought to account for the putative beneficial effects of statins toward neurodegenerative diseases. Does this mean that patients at risk for dementia should all run out and take statins? Unfortunately, the answer is negative. The problem lies with the chasm between experimental work and clinical trials. Despite a wealth of cogent and consistent evidence that statins should protect against dementia, two different prospective clinical trials of atorvastatin and simvastatin failed to produce any neuroprotective benefit to subjects with moderate AD. These studies are not formally published, but the atorvastatin work was presented at the AAN meeting in 2008 (the LEADE study) and the simvastatin work was presented at the ICAD meeting in 2008 (the CLASP study). The reasons for the discordance between laboratory studies, epidemiological studies, and prospective clinical trials remain unclear. One possibility is that the etiology of dementia is more complicated than reflected in the animal or epidemiological models. A possibility is that disease progression is too entrenched to halt or reverse by the time patients
receive a diagnosis of dementia. The latter hypothesis might be consistent with a modified amyloid-cascade hypothesis, in which patients with dementia have a brain burden of -amyloid (A) that is too extensive to allow statins to slow down neurodegeneration. Alternatively, damage to the cerebral vasculature, due to A or atherosclerosis, might be too extensive by the time dementia is diagnosed to provide sufficient blood flow, even if statins are prescribed. The vascular damage hypothesis suggests that agents that protect the cerebrovasculature might also be effective for treating or preventing dementia. In this context, we have recently shown that antihypertensive medications that modulate the renin-angiotensin system show a particularly strong association with reduced incidence of dementia and reduced rates of nursing home admissions among subjects with dementia (Li et al., 2009). One common property of statins and RAASdirected medications (ACE inhibitors and angiotensin receptor blockers) might be the ability to maintain the cerebrovasculature and cerebral blood flow. Future studies will need to test whether the primary site of action for RAAS-directed medications lies at the level of the vasculature or brain cells (neurons and astrocytes).
May 2010 | Volume 4 | Issue 1 | 93
bRAIN FOOD AND VITAMIN D

by William b. Grant
An additional contributing factor to AD is the genetic risk based on apolipoprotein 4 (ApoE4), which increases both cholesterol and insulin production (and weight in conjunction with a high-energy diet). ApoE4 is an important consideration for African Americans. The 1997 study noted that because AD patients brains have elevated concentrations of aluminum and transition metal ions, along with a reduced concentration of calcium, the dietary findings were consistent with a lower pH level in the digestive tract. The metals hypothesis, i.e., metalcatalyzed hydroxyl radicals damage neurons, has gained considerable support (Bush and Tanzi, 2008). Although dealing with the aftermath of a long-term unhealthy diet by using chelation therapy or drugs might be indicated, eating with brain and general health in mind seems a more reasonable and practical measure. Vitamin D is the current wonder compound, gaining increasing recognition for reducing the risk of many chronic and infectious diseases and mortality rates. Recently, interest has also extended to studying vitamin Ds benefits for the brain. Several recent observational studies reported an inverse correlation between prevalence of cognitive impairment and serum 25-hydroxyvitamin D [25(OH)D] levels, such as one in the UK (Llewellyn et al., 2009). In this study, a serum 25(OH) D level in the lowest quartile (312 ng/ml) was correlated with an odds ratio of cognitive impairment of 2.3 (95% confidence interval, 1.43.8) compared with those in the fourth quartile (2668 ng/ml) after adjustment for confounding factors. Because cognitive impairment is often a precursor of dementia, it is reasonable to expect that low serum 25(OH)D levels would also be a risk factor for dementia (Grant, 2009). Other diseases that seem to precede dementia, and for which risk increases with lower serum 25(OH)D levels, include cardiovascular disease, diabetes, and tooth loss from either dental caries or periodontal disease (Grant, 2009). On the basis of cross-sectional and observational studies, and randomized controlled trials of non-neurological diseases, serum 25(OH)D levels of 4060 ng/ ml are considered optimal. For each 1000 International Units (IU)/day of vitamin D production or oral intake, serum 25(OH) D levels increase by 610 ng/ml. Because mean population serum 25(OH)D levels range from 16 to 30 ng/ml, 20004000 IU/
William b. grant obtained a Ph.D. in Physics, University of California, Berkeley, in 1971. His professional career was devoted to developing and using laser systems for the remote sensing of atmospheric constituents such as aerosols and ozone, including 15 years with the NASA Langley Research Center. In Virginia, he performed an ecological study of the effects of acid rain on eastern hardwood forests, which led to his seminal paper on diet and Alzheimers disease. He turned his attention to the health benefits of vitamin D in 2000, moved to San Francisco, and founded SUNARC in 2004. wbgrant@infionline.net
An ecological study found total fat intake, along with total energy supply, highly correlated with Alzheimers disease (AD) prevalence with fish and cereals inversely correlated (Grant, 1997). These findings initiated the AD-dietary hypothesis, which continues to gain support. For example, a recent study in Poland found that the AD dietary pattern was characterized by a high intake of processed meat, butter, high-fat dairy products, eggs, and refined sugar, while the control pattern was characterized by a high intake of grains and vegetables (Gustaw-Rothenberg, 2009).
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day of vitamin D from UV-B irradiance and/or oral intake would be indicated. Thus, there appear to be two good ways to reduce the risk of cognitive impairment and dementia: diet modification and increased vitamin D. Acknowledgments I receive funding from the UV Foundation (McLean,VA), the Vitamin D Society (Canada), the Sunlight Research Forum (Veldhoven), and Bio-Tech-Pharmacal (Fayetteville, AR).
RefeRences
Bush, A. I., and Tanzi, R. E. (2008). Therapeutics for Alzheimers disease based on the metal hypothesis. Neurotherapeutics 5, 421-432. Grant, W. B. (1997). Dietary links to Alzheimers disease. Alz. Dis. Rev. 2, 42-55. (http://www.sunarc. org/JAD97.pdf) Grant, W. B. (2009). Does vitamin D reduce the risk of dementia? J. Alzheimers Dis. 17, 151-159. Gustaw-Rothenberg, K. (2009). Dietary patterns associated with Alzheimers disease: population based study. Int. J. Environ. Res. Public Health 6, 1335-1340. Llewellyn, D. J., Langa, K. M., and Lang, I. A. (2009). Serum 25-hydroxyvitamin D concentration and cognitive impairment. J. Geriatr. Psychiatry Neurol. 22, 188-195.
MODElS OF ThAlAMOCORTICAl CIRCUITRy TO INVESTIGATE NEURODEGENERATION

by Damien Coyle, liam P. Maguire and T. Martin McGinnity
The thalamus plays a major role in generating the many rhythms in electroencephalography (EEG), which change substantively during neurodegeneration (Cantero et al., 2009); yet, little is known about the role of the thalamus in neurodegeneration and whether thalamus atrophy is a primary or secondary phenomenon to hippocampal or neo cortical loss in Alzheimers disease (AD). De Jong et al. (2008) robustly observed reduced volumes of putamen and thalamus in patients diagnosed with probable AD in an MRI study of 139 memory complainers (MC), and suggest that degenerative pathology affects these structures more, or earlier, in AD than other deep gray matter structures. We are developing lumped circuit models of thalamocortical systems based on the work of Lopes da Silva et al. (1976) and Suffczynski (2000). Lumped circuit models reproduce neurophysiological signals at the macroscopic level allowing the model output to be compared to local field potentials (LFPs) or EEG. The model is set at the intermediate hierarchical scale between single cell and population level,
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RefeRences
Cantero, J. L., Atienza, M., Gomez-Herrero, G., Cruz-Vadell, A., Gil-Neciga, E., RodriguezRomero, R., and Garcia-Solis, D. (2009). Functional integrity of thalamocortical circuits differentiates normal aging from mild cognitive impairment. Hum. Brain Mapp. 30, 39443957. De Jong, L.W., van der Hiele, K., Veer, I. M., Houwing, J. J., Westendorp, R.G. J., Bollen, E. L. E. M., de Bruin, P.W., Middelkoop, H. A. M., van Buchem, M. A., and van der Grond, J. (2008). Strongly reduced volumes of putamen and thalamus in Alzheimers disease: an MRI study. Brain 131, 3277-3285. Izhikevich, E. M. and Edelman, G. M. (2008). Large-scale model of mammalian thalamocortical systems. PNAS 105, 3593-3598. Lopes da Silva, F. H., van Rotterdam, A., Parts, P., van Heudsen, E., and Burr, W. (1976). Models of neuronal populations: The basic mechanism of rhythmicity. Prog. Brain Res. 45, 281-308. Suffczynski, P. (2000). Neural dynamics underlying brain thalamic oscillations investigated with computational models, PhD Thesis, Warsaw University.
which allows establishment of the relationship between model parameters and both the cellular and synaptic properties of the modeled system. Lumped models have been used to investigate alpha rhythms, and to demonstrate that focal attention can be explored through assessing event related desynchronization and synchronization (ERD/ERS). These EEG characteristics can be used to study long term changes in oscillatory brain activity and short term memory storage/recall, and attention all of which are affected by AD, and thus lumped models of the thalamocortical systems are being studied in this context. Whilst lumped models offer many insights into thalamocortcial circuitry and rhythm generation in the brain, they are not suitable for elucidating synaptic connectivity at the microscopic scale. There is
Damien coyle, Ph.D., received a first class degree in Computing and Electronics Engineering and a doctorate in Intelligent Systems Engineering from the University of Ulster in 2002 and 2006, respectively, where he is now a Lecturer and a member of the Intelligent Systems Research Centres Computational Neuroscience Research Team (CNRT) and Brain-Computer Interface (BCI) team. His research interests include biosignal processing, bio-inspired cognitive, adaptive systems and BCI technology. More recently, he has been investigating computational models of neural systems and neurodegeneration related to Alzheimers disease. dh.coyle@ulster.ac.uk
significant evidence that AD is a synaptic disease. Izhikevich and Edelman (2008) have developed a more biologically realistic, large scale model of the thalamocortical systems in the mammalian brain. The shape and connectivity of the model was determined by MRI diffusion tensor imaging (MRI-DTI) data and knowledge of various neuron types in each cortical layer obtained from human studies and animal models. Neuronal dynamics of individual neuron and dendritic tree formations are based on a simple phenomenological model with short term synaptic plasticity and long term synaptic weighting via spike time dependent plasticity (STDP) also incorporated in the model. Other neuromodulation systems, including the dopaminergic reward systems and cholinergic systems (important for AD research), were also modeled.
liam p. Maguire, Ph.D., received his M.Eng. and Ph.D. degree in Electrical and Electronic Engineering from the Queens University of Belfast, UK, in 1988 and 1991, respectively. Prof. Maguire is currently Head of the School of Computing and Intelligent Systems at the University of Ulster. He also leads the Bio-inspired and Neuro-engineering team (BISNE) in the Intelligent Systems Research Centre. His research interests include fundamental research in bio-inspired intelligent systems (such as computationally effective spiking neural networks) and applying computational intelligence in different domains. lp.maguire@ulster.ac.uk
The model exhibits spatiotemporal dynamics and collective waves of oscillations of local field potentials in the delta, alpha and beta ranges, similar to those observed in the normal brain; even though, these were not specifically built into the model. Therefore, this model can also be used to investigate changes in rhythmic activity and how this may be affected due to synaptic loss and thalamus atrophy, as well as cholinergic innervation, which is known to be affected during and/or at the onset of AD. By using MRI-DTI of AD patients for model development, the influence of connectivity alone on brain dynamics may be investigated. A new Computational Neuroscience Research Team (CNRT) established at the University of Ulster aims to focus on these modeling approaches to study how thalamocortical circuitry effects or is affected by AD.
t. Martin Mcginnity, Ph.D., holds a first class honours degree in Physics, and a doctorate from the University of Durham, is a Fellow of the IET, senior member of the IEEE, and a Chartered Engineer. Prof. McGinnity is currently Director of the Intelligent Systems Research Centre at the University of Ulster, which encompasses the research activities of over 85 researchers, and is the author/co-author of over 200 research papers. His current research interests are focused on the creation of bioinspired intelligent computational systems which explore and model biological signal processing. tm.mcginnity@ulster.ac.uk
NEUROlOGICAl AND PERIPhERAl INFlAMMATION: ThE DARK AND lIGhT SIDES OF A TWO-WAy SySTEM IN NEURODEGENERATION
by Andrea Malaspina and Egle Solito
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RefeRences
Beal, M. F. (2003). Mitochondria, oxidative damage, and inflammation in Parkinsons disease. Ann. N. Y. Acad. Sci. 991, 120-131. Kamer, A. R., Craig, R. G., Dasanayake, A. P., Brys, M., Glodzik-Sobanska, L., and de Leon, M. J. (2008). Inflammation and Alzheimers disease: possible role of periodontal diseases. Alzheimers Dement. 4, 242-250. Lucas, S. M., Rothwell, N. J., and Gibson, R. M. (2006). The role of inflammation in CNS injury and disease. Br. J. Pharmacol. 147 Suppl. 1, S232-240. Perry, V. H., Cunningham, C., and Holmes, C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161-167. Ravits, J. (2005). Sporadic amyotrophic lateral sclerosis: a hypothesis of persistent (non-lytic) enteroviral infection. Amyotroph. Lateral Scler. 6, 77-87.
In the last decade, the phenomenon of exchange and circulation of immune mediators between the central nervous system (CNS) and the extraneural compartments has been progressively unearthed and characterized. It has become increasingly clear that any inflammatory process, initiated by endogenous or exogenous pathological determinants on either side, is likely to have broad effects beyond the compartment of origin (Lucas et al., 2006; Perry et al., 2007). For example, the changes in the microenvironment of circulating components of the immune system induced by a neurodegenerative process like amyotrophic lateral sclerosis (ALS) (Ravits, 2005) are characterized by the reduction of circulating CD8+
Andrea Malaspina graduated from the University of Pavia, Medical School, Italy, and obtained his Ph.D. at Imperial College London. He is Consultant Neurologist and Honorary Senior Lecturer at the Institute of Cell and Molecular Science, Barts, and the London NHTrust/Basildon University Foundation. His main area of research is ALS and motoneuron diseases. a.malaspina@qmul.ac.uk egle solito obtained her Ph.D. at the University of Pavia, Italy. She is Senior Lecturer in Molecular and Cellular Pharmacology at Imperial College London, and her main research focuses on the impact of peripheral inflammation in neurodegeneration, with particular interest in developing pharmacological tools for the diagnosis and treatment of inflammatory conditions. e.solito@imperial.ac.uk
T lymphocytes, of CD4+CD25+ regulatory T (Treg) cells, and of monocytes (CD14+) in early stages of the disease, as a result of their early recruitment into the CNS in the unfolding of the disease pathology. In ALS and other neurodegenerative disorders, like Alzheimers and Parkinsons disease, activation of resident microglia, which is linked to a change in the expression profile of circulating monocytes and chemokines, is an additional example of the systemic effect of neuroinflammation (Beal, 2003; Kamer et al., 2008). In the opposite direction, the effects on the progression of these neurodegenerative conditions caused by traumatic and infective stressors are well documented on a clinical level, whilst the immunobiology of this pathological transfer is far from being understood. These observations raise two main questions of potential interest for human health: a) what are the biological mechanisms supporting the two-way propagation of inflammatory processes between the CNS and the non-neuronal systems, and how do environmental stressors, such as systemic inflammation, impact upon the development of neurodegenerative disorders; and b) whether the early changes in the relative proportion of immune cells and mediators induced by the most common neurological conditions reported above, may be reliably detected and used as potential biomarkers of disease initiation, clinical progression or as surrogate markers for treatment efficacy.
A more cohesive picture of how systemic inflammatory stimuli, such as infection, trigger an inflammatory CNS response has recently emerged. The cells that respond fastest to these challenges with a consistent production of pro-inflammatory mediators (cytokines, lipid metabolites, free radicals) are components of the brains innate immune system (microglia, and resident macrophages). As part of the host-defence process, this stimulates autonomic, neuroendocrine and behavioral responses that promote recovery. Under normal conditions, the neuroinflammatory response resolves and microglia resume their resting role of monitoring the microenvironment. However, increasing experimental and clinical evidence indicates that systemic inflammation can worsen, or possibly even trigger, neurological diseases where it is established that a sustained innate immune response in affected brain areas contributes to the pathogenic process. Although the underlying mechanisms are not clear, mounting evidence suggests that microglia enter a primed/hypersensitive state in these neurodegenerative conditions. Priming of microglia may lead in turn to an exaggerated production of toxic pro-inflammatory mediators in response to systemic inflammogens, thereby exacerbating neuronal loss. For treatment purposes, the reduction of microglial activation may represent a powerful strategy to limit CNS inflammation and degenerative disease progression.
ThE NEW ERA OF hORMONES IN NEURODEGENERATION

by Natalia Crespo-biel3, hyunjin Kim1, Mark A. Smith2 and Gemma Casadesus1
During the last 30 years, the beneficial effect of estrogen on the CNS has predominantly driven the field of hormones and neurodegeneration. Seminal studies by McEwen, Pfaff, Gibbs, Sherwin and others have demonstrated the benefits of estrogen on synaptic plasticity and cognition, its ability to modulate of acetylcholinergic proc1
female sex hormone. Polarised light micrograph of -estradiol crystals.
Department of Neurosciences. Case Western Reserve University. Cleveland, OH, USA Department of Pathology. Case Western Reserve University. Cleveland, OH, USA Department of Human Genetics. Katholieke Universiteit Leuven. Leuven, Belgium
esses, and to produce positive effects on cognition in menopausal women. These findings collectively suggested that a largescale randomized trial on hormone replacement (HRT) effects on cognition would be a blinding success. However, to the surprise of the field, the Womens Health Initiative Study (WHIS) demonstrated otherwise. In older women, HRT has no impact on cognition and leads to a higher risk of dementia (Rapp et al., 2003; Shumaker et al., 2004). While the results of these studies were considered by many as a setback, something extraordinary has come out of it. The field
has been forced to search deeper into estrogen-related molecular mechanisms, the formulation of HRT, and into understanding the HRT timing CNS effects. Also, and in our opinion of primary importance, it has broadened the focus of hormonal effects on the brain and allowed novel non-estrogen related hypotheses to emerge. Recent studies by Brinton and colleagues demonstrate that estrogen has differential effects when administered in young or old neurons and Daniel and colleagues have shown that the impact of estrogen on cognition and plasticity processes is intimately
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A
60
b
90 80 50 ac 70 60 freezing (%) a 30 a 20 ac 50 40 30 20 10 Sham E2+LH E2 0 1 2 Day 3 4 0 Context Altered Cued 10 ac ac Sham E2+LH E2 ab
40 escape time (sec)
figure 1. Cognitive performance in the fear conditioning (A) and Morris water maze tasks (MWM) (B) in ovariectomized mice treated with 17 estradiol (E2), 17 estradiol + LH, compared to SHAM operated controls. (A) E2+LH treated animals are significantly cognitively impaired compared to 17 estradiol (c) and SHAM (a) operated controls during MWM training (p<0.05). 17 estradiol replaced animals are significantly impaired compared to SHAM control animals (a) (p<0.05). (b) E2+LH treated animals show significantly less contextual fear conditioning compared to E2 (c) and SHAM control (a) groups. Long-term continuous 17 estradiol treatment increases cued fear conditioning compared to SHAM controls (a) and E2+LH normalizes 17 estradiol treatment response to SHAM control levels (b).
related to administration timing and/or age. Furthermore, Hogervorst has implicated secondary hormonal mechanisms, such as high levels of SHBG in Alzheimers disease (AD). Given that negative feedback of estrogen onto GnRH and gonadotropin release diminishes as we age (Weiss et al., 2004), a hypothesis that may link these important studies is that the benefits of estrogen during the critical period may be, at least partially, related to the ability of estrogen to modulate other hormones of the hypothgemma casadesus received her Ph.D. in Physiological Psychology from Tufts University in 2003. Following a Post-doctoral Fellowship in the Department of Pathology at Case Western Reserve University, she was recruited as a faculty member and Director of the CWRU Rodent Behavior Core at the Department of Neurosciences in 2007. Her research focuses on the switch mechanisms that drive normal aging toward a pathogenic age-related condition, such as Alzheimers disease (AD). Dr. Casadesus serves on various editorial boards and has authored over 70 peer-reviewed manuscripts and chapters in the fields of aging and AD. gxc40@case.edu
alamic-pituitary-axis, namely GnRH or gonadotropins, such as LH. Emerging data supports a role for gonadotropins on cognition and AD, both clinically (Rodrigues et al., 2008) and pre-clinically (Bryan et al., 2010). Furthermore, increased levels of serum gonadotropins such as luteinizing hormone (LH), lead to hippocampal cognitive deficits in the presence of estrogen in rodents (Figure 1). Taken together, the WHIS has provided a unique and exciting opportunity to catapult the study of hormones in the brain and their role on neurodegeneration to the next level of excellence. The field has been re-energized with novel ideas that are leading to a more global understanding of hormones in the brain. Importantly, one exciting aspect that will likely play a significant role in uncovering the role of hormones in neurodegeneration is the study of endogenous production of hormones in the brain, their autocrine/ paracrine signaling, and their significance to neuronal function/malfunction. These studies will undoubtedly drive novel hormonebased therapies that can more effectively prevent neurodegenerative disease.
RefeRences
Bryan, K. L., Mudd, J. C., Richardson, S. L., Chang, J., Lee, H. G., Zhu, X., Smith, M. A., and Casadesus, G. (2010, in press). Downregulation of Serum Gonadotropins is as Effective as Estrogen Replacement at Improving Menopause-Associated Cognitive Deficits. J. Neurochem. Rapp, S. R., Espeland, M. A., Shumaker, S. A., Herderson, V. W., Brunner, R. L., Manson, J.-A. E., Gass, M., L. S., Stefanick, M. L., Lane, D. S., Hays, J., et al. (2003). Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Womens Health Initiative Memory Study: a randomized controlled trial. Jama 289, 2663-2672. Rodrigues, M. A., Verdile, G., Foster, J. K., Hogervorst, E., Joesbury, K., Dhaliwal, S., Corder, E. H., Laws, S. M., Hone, E., Prince, R., et al. (2008). Gonadotropins and cognition in older women. J. Alzheimers Dis. 13, 267-274. Shumaker, S. A., Legault, C., Kuller, L., Rapp, S. R., Thal, L., Lane, D. S., Fillit, H., Stefanick, M. L., Hendrix, S. L., Lewi, C. E., et al. (2004). Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Womens Health Initiative Memory Study. Jama 291, 2947-2958. Weiss, G., Skurnick, J. H., Goldsmith, L. T., Santoro, N. F., and Park, S. J. (2004). Menopause and hypothalamic-pituitary sensitivity to estrogen. Jama 292, 2991-2996.
INTRACEllUlAR PROTEIN DEGRADATION AND ChRONIC NEURODEGENERATIVE DISEASE

by lynn bedford1, Simon Paine1, James lowe1 and R. John Mayer1
It was shown over 21 years ago that all the chronic neurodegenerative diseases demonstrate intraneuronal inclusions that contain ubiquitylated proteins (Lowe et al., 1988). The reason for the accumulation of ubiquitylated proteins in these deposits is still not completely understood, but molecular studies point toward a central role of the ubiquitin proteasome system (UPS), autophagy and inclusion body formation in neuronal survival in these neurological illnesses. Protein ubiquitylation is a major post-translational modification with key roles in the regulation of cellular homeostasis including processes such as 26S proteasome-mediated degradation of ubiquitin-protein conjugates, autophagy and endocytosis. Diseaseassociated aggregation-prone proteins like -synuclein undergo a transition from monomers, through oligomers to form aggregates that are sequestered eventually in neuronal inclusions, which are probably neuropathological homologues of experimentally-induced cellular aggresomes.
1
In recent years, conditional gene targeting in mice, ablating either a 26S proteasomal ATPase gene (Bedford et al., 2008) or two autophagy genes, triggered neurodegeneration in the brain (Hara et al., 2006; Komatsu et al., 2006). The fact that neurodegeneration occurs when either the UPS or autophagy are genetically prevented in mice strongly suggests that in humans the neuronal protein degradative systems are overwhelmed or malfunction in chronic neurodegenerative disease and not that the amyloidogenic proteins per se cause neurodegeneration. Intraneuronal (and extraneuronal) deposits of amyloidogenic
r. John Mayer has studied intracellular proteolysis including autophagy and the ubiquitin proteasome system for 40 years; particularly in relation to chronic neurodegenerative disease. He discovered the cellular perinuclear protein isolation site, later described as the aggresome, by protein microinjection studies. This discovery led to the finding that proteins in neuronal inclusions in chronic neurodegenerative disease were ubiquitylated, including cortical Lewy bodies, and to the appreciation of the importance of dementia with Lewy bodies in dementia. john.mayer@nottingham.ac.uk
School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham, UK
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proteins may be a consequence and not a cause of neurodegeneration, i.e., produced in neurons with compromised proteolytic systems! The ubiquitin-dependent progression of events in a single neuron leading to neuronal death may occur as follows. The degradation of ubiquitylated proteins by the UPS is compromised by the propensity of some proteins to undergo conformation change to aggregate-prone oligomers and polymers, some of which inhibit the activities of the 26S proteasome. However, ubiquitylation of proteins in higher order structures attracts ubiquitin-binding proteins including p62 and NBR1 that also bind to the autophagosome membrane-anchored LC3/GABARAP/ ATG8 protein to target the ubiquitylated proteins for degradation in autophagolysosomes. Subsequently, as these degradative systems become saturated, ubiquitylated
proteins, together with other proteins and organelles, e.g., mitochondria, migrate to perinuclear inclusions (Bedford et al., 2008). Mitochondrial involvement may be central to some neurodegenerative diseases. There is increasingly evidence from unrelated approaches, independent of studying neurodegenerative disease, to support the notion that protein ubiquitylation and autophagy can combine to eliminate unwanted and dangerous ubiquitylated proteinaceous particles from cells. For example, the ubiquitylation of intracellular bacterial proteins is involved in innate immunity to destroy intracellular bacteria in autophagolysosomes (Zheng et al., 2009). Focus is now needed on the cellular signaling systems that regulate the UPS, autophagy and inclusion body formation so that therapeutic targets to slow or prevent neuronal death can be identified.
yeast enzyme. Molecular model of an enzyme from Saccharomyces cerevisiae (Bakers yeast).
RefeRences
Bedford, L., Hay, D., Devoy, A., Paine, S., Powe, D. G., Seth, R., Gray, T., Topham, I., Fone, K., Rezvani, N., et al. (2008). Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J. Neurosci. 28, 8189-8198. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884. Lowe, J., Blanchard, A., Morrell, K., Lennox, G., Reynolds, L., Billett, M., Landon, M., and Mayer R. J. (1988). Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinsons disease, Picks disease, and Alzheimers disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease. J. Pathol. 155, 9-15. Zheng, Y. T., Shahnazari, S., Brech, A., Lamark, T., Johansen, T., and Brumell, J. H. (2009). The Adaptor Protein p62/SQSTM1 Targets Invading Bacteria to the Autophagy Pathway. J. Immunol. 183, 5909-5916.
RESTORATIVE CEll ThERAPIES IN NEURODEGENERATION

by Alberto Martnez-Serrano
Recent advances in the understanding of stem cell biology and gene intervention are paving the way for the future application of these technologies in the treatment of neurological conditions. However, several challenges remain, and overcoming them seems essential for the development of competitive therapies. Among them are: choice of the right neuroprotective and/or cell replacement strategy (or their combination), clarification and control of the precise fate and function of transplanted cells, the hosts immune response to foreign material, and, most notably, the safety of these procedures. Some of these crucial aspects can be exemplified using the case of Parkinsons disease, in which researchers have managed to generate dopaminergic neurons of the type that degenerates in the disease (substantia nigra neurons) from both embryonic stem (ES) cells and ventral mesencephalic neural stem cells. Although the ventral mesencephalon is acknowledged as the best source of genuinely instructed/patterned stem cells ready to differentiate into the proper type of neurons their growth
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Alberto Martnez-serrano, Ph.D., graduated in Biochemistry and Molecular Biology from the Universidad Autnoma de Madrid (UAM) in 1986. After completing his Ph.D. (1990) in Agingrelated Neurodegeneration, he worked as a visiting scientist at the University of Lund (Sweden) where he developed gene and cell therapy procedures for the amelioration of cognitive deficits in aged animals. At present he is Associate Professor of Biochemistry and Molecular Biology (UAM), interested in the basic biology of human neural stem cells and their therapeutic applications. amserrano@cbm.uam.es
and stability in vitro is very poor, which complicates the development of a cellular product for routine therapy. This can be overcome by a process called immortalization, which extends the life-span of the cultures, making them amenable for research and the development of cell products. In addition to yielding a well-controlled cell source, immortalization has shown to be safe in research animals, where tumors from karyotypically normal cells have never been reported. However, the theoretical concern still remains for some investigators. Alternatively, ES cells (and induced pluripotent stem cells; iPSCs) can apparently grow without restrictions in culture and can be differentiated, which, in most cases, generates the cells of interest. However, it is clear from many studies that the cells are difficult to control in vivo, the transplants give rise to unwanted tumors in some cases, and, in general, overgrowth
and continued proliferation of a substantial number of cells occurs. Thus, efforts in the field are focused on understanding key processes controlling the proliferation and phenotypic stability of neural stem cells, and the purification/isolation of the correct cells from preparations of partially differentiated embryonic stem cells; although, this has been reported to compromise survival of the potentially safe and clean cells. Since safety of ES cells is clearly a problem, another interesting strategy would be the use of suicide genes, which would allow us to kill any dividing cell that originated from a transplant (as long as optimally controlled expression systems specific for the proliferative cell, and drugs with pharmacokinetics good enough to reach all the undesired cells, are developed). Conceptually, the need for purification or the use of suicide genes implies that pluripotent stem cells
are not safe. In this context, the recently described iPSCs, generated by reprogramming adult cells, deserve to be mentioned. iPSCs are derived from adult tissue, clearly escape the ethical concerns surrounding ES cells, and provide an immunologically compatible cell source. However, the obstacle is virtually the same as with ES cells: that is, controlling their proliferation and optimizing their differentiation in other words, efficacy and safety. In summary, the future clinical development of cell therapies for neurodegenerative diseases requires a tremendous and parallel effort to solve the problem of safety of the easiest-to-grow cell source (ES or iPS cells) or what perhaps is more likely to occur the refinement of procedures for handling already instructed neural stem cells obtained from the nervous system, which, by default, produce only the desired neural cell types.
IllUMINATING POlyPhENOlS IN NEURODEGENERATION

by hayley C. Fivecoat and Giulio M. Pasinetti
Currently, there is no cure or preventive treatment for Alzheimers disease (AD) and other dementias. Thus, an urgent need exists to find a means for preventing and treating neurodegenerative diseases. In the US, billions of dollars are spent each year on treating chronic illnesses such as AD; yet, the majority of these conditions are preventable by making healthy lifestyle choices. One primary and relevant component of a healthy lifestyle is ones diet and nutrient intake. Evidence supporting the link
between nutrition and neurodegeneration is growing, especially as relevant mechanistic pathways and biochemical functions are illuminated. Thus, many researchers are actively investigating the potential role of dietary factors in neurodegenerative conditions. The growing link between diet and disease has created an unprecedented demand for foods or therapeutic food products that help prevent or manage health conditions. Recent studies by sci-
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RefeRences
Heo, H. J., Choi, S. J., Choi, S. G., Shin, D. H., Lee, J. M., and Lee, C. Y. (2008). Effects of banana, orange, and apple on oxidative stress-induced neurotoxicity in PC12 cells. J. Food Sci. 73, H28-32. Ho, L., Yemul, S., Wang, J., and Pasinetti, G. M. (2009). Grape seed polyphenolic extract (GSE) as a novel potential therapeutic agent in tauopathies. J. Alzheimers Dis. 16, 433-439. Luchsinger, J. A., Tang, M. X., Siddiqui, M., Shea, S., and Mayeux, R. (2004). Alcohol intake and risk of dementia. J. Am. Geriatr. Soc. 52, 540 546. Lau, F. C., Shukitt-Hale, B., and Joseph, J. A. (2007). Nutritional intervention in brain aging: reducing the effects of inflammation and oxidative stress. Subcell. Biochem. 42, 299318. Wang, J., Ho, L., Zhao, W., Ono, K., Rosensweig, C., Chen, L., Humala, N., Teplow, D. B., and Pasinetti, G. M. (2008). Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimers disease. J. Neurosci. 18, 6388-6392.
entists with expertise in AD, dementia and nutrition have identified bioactive natural compounds from foods that might provide beneficial AD-modifying activities. In particular, there is a large amount of evidence that polyphenolic compounds found in certain fruits may exert their beneficial effects through signal transduction and neuronal communication (Lau et al., 2007). Further, recent studies confirm that polyphenol-rich fruits prevent oxidative stress in an in vitro model of AD (Heo et al., 2008). In addition, moderate consumption of red wine, rich in polyphenols, has been implicated as a healthy dietary lifestyle for the prevention of AD (Luchsinger et al., 2004). In light of this evidence, we conducted several studies on the role of grape seed derived polyphenolic extract (GSPE) in
Hayley c. fivecoat is a graduate from the State University of New York at Stony Brook with a degree in psychology. Since joining Dr. Pasinettis laboratory, her research interests have been primarily focused on the cognitive impairments associated with neurodegenerative conditions, neuropsychological rehabilitation and alternative and preventive medicine, which has been a great contribution to the translational research program in Mount Sinai School of Medicines Center of Excellence for Novel Approaches to Neurotherapeutics. hayley.fivecoat@mssm.edu
AD neuropathology, in particular on the abnormal accumulation of extracellular -amyloid (A) oligomers and intracellular tau peptides. Specifically, we found that GSPE significantly inhibits the aggregation of A proteins to high molecular weight oligomers in vitro, and significantly attenuates cognitive deterioration and reduces oligomeric A content in vivo (Wang et al., 2008). We also found that the GSPE is capable of inhibiting the aggregation of tau peptides and dissociating pre-existing tau aggregates in vitro (Ho et al., 2009). Collectively, this evidence from pre-clinical models indicates that GSPE may provide disease-modifying bioactivity in A- and tau-mediated neurodegenerative disorders such as AD. In view of this evidence, the effects of the GSPE on neurodegeneration in
giulio M. pasinetti, renowned expert in neurodegeneration, serves as Director of the Center of Excellence for Novel Approaches to Neurotherapeutics and the Saunders Family Professor of Neurology, and is a Professor of Neurology, Psychiatry, Neuroscience and Geriatrics and Adult Development at Mount Sinai School of Medicine. He also serves as Director of Basic and Biomedical Research and Training, Geriatric Research, Education and Clinical Center, and of Translational Neuroscience Laboratories at the James J. Peters Veterans Affairs Medical Center. giulio.pasinetti@mssm.edu
pre-clinical models strongly support further investigation on its preventive and therapeutic properties for AD and other dementias. In addition, should further studies confirm these effects, these findings would not only positively impact the field of AD, but also of other neurodegenerative conditions marked by A and/or tau neuropathologies (e.g., progressive supranuclear palsy). It is important to note that the potential use of GSPE in treatments for humans is based on studies in preclinical models of AD, and must be rigorously tested in clinical trials in order to validate any claims as a clinical treatment. Nevertheless, the findings thus far on GSPE have been very exciting and hold promise in further investigations as a novel preventive and therapeutic agent in AD and other neurodegenerative conditions.
AbNORMAl MITOChONDRIAl DyNAMICS AND NEURODEGENERATION

by Xiongwei Zhu
The brain is a highly metabolic tissue, and neurons in the central nervous system have an intense demand for mitochondria. On top of this, compared to other cell types, the complex morphology of neurons leads to functional heterogeneity in neuronal segments, thus translating into different local demands for energy and calcium buffering. Therefore, neurons are not only vulnerable to mitochondrial dysfunction, but also particularly sensitive to changes in mitochondrial movement and distribution. Mitochondria are highly dynamic organelles that constantly divide and fuse with each other (Chan, 2006). In fact, this highly dynamic balance of mitochondrial fission and fusion not only controls mitochondrial morphology and number, but also regulates mitochondrial function and distribution. Therefore, it is not surprising that alterations in mitochondrial fission and fusion significantly impact neuronal function. Mitochondrial dysfunction is a prominent feature of Alzheimers disease (AD) neurons, yet the underlying mechanisms remain elusive. We hypothesized that an abnormal mitochondrial dynamic causes mitochondrial dysfunction and abnormal distribution, which, in turn, causes neuronal dysfunction in AD. Indeed, we found mitochondrial dynamics is tipped toward enhanced fission in susceptible neurons in AD brain and in fibroblasts from AD patients (Wang et al., 2008a; Wang et al., 2009). Moreover, in contrast to the observation that mitochondria are distributed throughout the soma and processes in neurons from control cases, mitochondria density in neurites is much lower in AD neurons. Such an abnormal mitochondrial distribution is likely a consequence of alterations in the expression of mitochondrial fission and fusion proteins, and further causes synaptic dysfunction in neuronal cells. Mutations of amyloid precursor protein (APP) cause familial AD and it is believed that -amyloid (A) is the culprit of the disease. In fact, overexpression of APP mutant or treatment of cells in vitro with soluble A oligomers causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentaxiongwei zhu received his Ph.D. in 2002 from the Department of Pathology at Case Western Reserve University. He was a Post-doctoral Fellow and Instructor in Pathology until he became Assistant Professor in 2004 and Associate Professor in 2009. Dr. Zhu is internationally known for his work in mitochondrial dysfunction in neurodegenerative diseases and is the recipient of many awards, including the International Junior Investigator Award from International College of Geriatric Psychoneuropharmacology and the Young Scientist Lectureship Award from the International Society for Neurochemistry. xiongwei.zhu@case.edu
RefeRences
Chan, D. C. (2006). Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241-1252. Su, B., Wang, X., Zheng, L., Perry, G., Smith, M. A., and Zhu, X. (2009) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim. Biophys. Acta doi:10.1016/j.bbadis.2009.09.013 Wang, X., Su, B., Fujioka, H. and Zhu, X. (2008a). Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimers disease patients. Am. J. Pathol. 173, 470-482. Wang, X., Su, B., Siedlak, S., Moreira, P., Fujioka, H., Wang, Y., Casadesus, G. and Zhu, X. (2008b). A Overproduction Causes Abnormal Mitochondrial Dynamics via Modulation of Mitochondrial Fission/Fusion Proteins. Proc. Natl. Acad. Sci. USA 105, 19318-19323. Wang, X., Su, B., Lee, H. G., Li, X., Perry, G., Smith, M. A., and Zhu, X. (2009). Impaired balance of mitochondrial fission and fusion in Alzheimers disease, J. Neurosci. 29, 9090-9103.
tion and reduced mitochondrial density in neuronal processes (Wang et al., 2008b; Wang et al., 2009). Interestingly, soluble A oligomers also induce synaptic dysfunction, which is well correlated with abnormal mitochondrial distribution. More importantly, overexpression of mitochondrial fission protein DLP1 repopulates neuronal processes with mitochondria and prevents soluble A oligomer-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in soluble A oligomer-induced
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synaptic abnormalities. Overall, our recent studies, along with others, demonstrated that an abnormal mitochondrial dynamic likely plays a critical role in the pathogenesis of AD. In fact, with the deeper understanding of the dynamic nature of mitochondria, characterized by a tightly controlled balance of fission and fusion, emerging evidence suggests that abnormal mitochondrial dynamics is involved in various neurodegenerative diseases. Given that mitochondrial dynamics significantly
impacts mitochondrial genome integrity and bioenergetics, as well as neuronal functions including synaptic maintenance and cell death, it is very likely that abnormal mitochondrial dynamics represents a key common pathway mediating or amplifying mitochondrial dysfunction and neuronal dysfunction during the course of neurodegeneration (Su et al., 2009). Therefore, strategies to modify abnormal mitochondrial dynamics may be an attractive therapeutic target for the treatment of neurodegenerative diseases.
CEll TO CEll TRANSMISSION OF SyNUClEINOPAThy: IS IT A KEy MEChANISM?

by Atsushi Takeda
More than ten years have passed since fetal nigral neurons were transplanted into the striatum of cases with Parkinsons disease. Recently, autopsy analyses of the long-term surviving cases were reported by several groups and, surprisingly, Lewy-like structures were demonstrated not only in the host brain tissues, but also in implanted neurons (Li et al., 2008; Kordower et al., 2008). These reports attracted much attention, because it was suggested that the pathological process in host brains might affect implanted tissues. In fact, six cases embryonic dopamine neurons were transplanted 9-16 years before were autopsied and among them three cases tested positive for Lewy-like structures in grafted neurons (Li et al., 2008; Kordower et al., 2008). Because long-term surviving cases tended to be positive for Lewy-like structures, aging of grafts might play a role. However, implanted fetal tissues were genetically different from
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Atsushi takeda, M.D., Ph.D., is a Neurologist and Neuroscience Researcher. He graduated from Tohoku University, School of Medicine (1985), and Tohoku University, Graduate School of Medicine (1992). He started his professional carrier as a Resident in Neurology in 1985. From 1998-2000, he studied in the Institute of Pathology, Case Western Reserve University. He is now an Associate Professor of Neurology at Tohoku University (2007-present). His main research interest focuses on the pathomechanism of synucleinopathies. atakeda@em.neurol.med.tohoku.ac.jp
host tissues and were still in their teenages at autopsy; it is plausible that host brains might directly facilitate pathological changes in the grafts. More recently, by using cultural cells or experimental animals, it was demonstrated that -synuclein (-Syn) expressed within neural cells may be excreted to extracellular spaces and then incorporated into other cells (Desplats et al., 2009). Such mechanisms may be able to explain the mecha-
nism by which glial-cytoplasmic inclusions in the multiple system atrophy are formed in oligodendroglia, in which -Syn is originally not expressed. These results strongly suggest that -Syn molecules are transported from cell to cell. Furthermore, it was also demonstrated that in transgenic mice, which overexpress neuronal -Syn, neural grafts derived from non-transgenic animals showed -Syn aggregation in neural cells and, in fact, parts of them demonstrated apoptosis (Desplats et al., 2009). Therefore, pathological species of -Syn molecules, which change conformation from amorphous to misfolded, may also be transported from cell to cell. Moreover, such pathological species may catalyze further conformational changes of nave -Syn molecules. Recently, risk genes in the sporadic Parkinsons disease were reported one after the other (Satake et al., 2009) and our knowledge of molecular mechanisms of nigral cell death is increasing. However, the results described here also suggest that once neurodegenerative processes start in neural cells, possibly triggered by genetic and/or environmental factors, they may autonomously propagate to their surrounding tissues. Such an autonomous pathophysiological process is similar to the case of the prion disease (Olanow and Prusiner, 2009) and may explain why early symptoms are
usually located within one side and then expand to the other side during the progression of diseases. Further research in this field will shed light on new aspects of the neurodegenerative process and hopefully provide us with new approaches to cure synucleinopathies.
RefeRences
Desplats, P., Lee, H.-J., Bae, E.-J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., and Lee, S.-J. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl. Acad. Sci. USA 106, 13010-13015. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B., and Olanow, C. W. (2008). Parkinsons disease pathology in long-term embryonic nigral transplants in Parkinsons disease. Nat. Med. 14, 504-506. Li, J.-Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J., Lashley, T., Quinn, N. P., Rehncrona, S., Bjrklund, A., et al. (2008). Lewy bodies in grafted neurons in people with Parkinsons disease suggest host-to-graft disease propagation. Nat. Med. 14, 501-503. Olanow, C. W., and Prusiner, S. B. (2009). Is Parkinsons disease a prion disorder? Proc. Natl. Acad. Sci. USA 106, 12571-12572. Satake, W., Nakabayashi, Y., Mizuta, I., Hirota, Y., Ito, C., Kubo, M., Kawaguchi, T., Tsunoda, T., Watanabe, M., Takeda, A., et al. (2009). Genomewide association study identifies common variants at four loci as genetic risk factors for Parkinsons disease. Nature Genet. 41, 1303-1307.
DEMENTIA WITh lEWy bODIES

by James F. Morley and John E. Duda
Standing beside the rubble of a collapsed building; it may be impossible to say what led to its demise. A similar challenge is often faced by physicians evaluating patients with dementia; regardless of the original underlying etiology, the end result may look much the same. Dementia with Lewy bodies (DLB) is the second most common dementing illness after Alzheimers disease (AD), accounting for as much as 20% of dementia, and can be difficult to distinguish from other causes, especially in later stages. Defined by a combination of cognitive dysfunction, visual hallucinations, Parkinsonism (rigidity, bradykinesia, tremor or gait disturbance) and fluctuating levels of consciousness, DLB is very similar to the dementia commonly seen in PD (PDD; Parkinsons disease with dementia). However, early and accurate diagnosis is important for prognosis and management, as DLB patients may suffer a more malignant course, and need to avoid specific medications, e.g., neuroleptics often used to treat hallucinations or psychosis in dementia. Clinical diagnosis hinges on a combination of specific cognitive deficits, associated neurologic signs or symptoms, and the order in which they appear. This approach has been recently summarized by the DLB/ PDD Working Group (Lippa et al., 2007) including the 1-year rule to distinguish PDD from DLB: cognitive dysfunction preceding or occurring within one year of incident Parkinsonism defines DLB, whereas cognitive dysfunction occurring in the context of well-established PD is diagnosed as PDD; although, for clinical purposes, the clinical situation should dictate what term to use. Cognitive dysfunction in DLB and PDD is characterized by relatively worse attention and executive dysfunction compared to the primarily amnestic syndrome commonly seen in AD. While such distinc-
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parkinsons disease. Colored transmission electron micrograph (TEM) of a section through a Lewy body in a nerve cell in the brain, a diagnostic feature of Parkinsons disease.
James f. Morley completed the M.D. and Ph.D. degrees at Northwestern University in Chicago followed by a neurology residency at the University of Pennsylvania. He is currently a Fellow in Movement Disorders at the University of Pennsylvania Health System. His research interests include the use of olfaction as a biomarker in neurodegenerative disease and advancing neuroimaging capabilities for the diagnosis of Parkinsons disease and related disorders. morleyj@uphs.upenn.edu
tions are apparent in group studies, their diagnostic value for individual patients is often limited, as substantial overlap occurs. Additionally, the relative lack of early memory deficits may lead to underdiagnosis of DLB or PDD, as recent studies suggest that the widely used Mini-Mental Status Exam (MMSE) is a relatively insensitive measure of cognitive dysfunction in PD (Mamikonyan et al., 2009). The current challenge is to determine what physiologic, biochemical or radiologic variables (collectively referred to as biomarkers) are predictive of important clinical outcomes or correlate with the true pathologic diagnosis. A common feature of neurodegenerative dementias is misfolding of native or mutated cellular proteins leading to aggregation and the appearance of intracellular inclusions (-synuclein containing Lewy bodies and neurites in DLB and PDD; amyloid plaques and tau neurofibrillary tangles in AD) that are increasingly recognized to coexist in these disorders. Recent advances in neuroimaging allow investigators to identify some of these elements in living patients. Pittsburgh Compound B (PiB), long used in positron emission tomography (PET)
John e. Duda received his M.D. from Jefferson Medical College and is currently the Director of the Parkinsons Disease Research, Education and Clinical Center at the Philadelphia Veterans Affairs Medical Center and an Assistant Professor of Neurology at the University of Pennsylvania School of Medicine. His research interests include investigating the neuropathology of Parkinsons disease and related disorders, the use of olfactory dysfunction as a biomarker in Parkinsons disease and development of novel therapeutics for neurodegenerative disease. john.duda@va.gov
RefeRences
Edison, P., Rowe, C. C., Rinne, J., Ng, S., Ahmed, I., Kemppainen, N., Villemagne, V. L., OKeefe, G., Ngren, K., Chaudhury, K. R., et al. (2008). Amyloid load in Parkinsons disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J. Neurol. Neurosurg. Psychiatry 17, 1331-1338. Gomperts, S. N., Rentz, D. M., Moran, E., Becker, J. A., Locascio, J. J., Klunk, W. E., Mathis, C. A., Elmaleh, D. R., Shoup, T., Fischman, A. J., et al. (2008). Imaging amyloid deposition in Lewy body diseases. Neurology 71, 903-910. Lippa, C. F., Duda, J. E., Grossman, M., Hurtig, H. I., Aarsland, D., Boeve, B. F., Brooks, D. J., Dickson, D. W., Dubois, B., and Emre, M. (2007). DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68, 812-819. Maetzler, W., Liepelt, I, Reimold, M., Reischl, G., Solbach, C., Becker, C., Schulte, C., Leyhe, T., Keller, S., Melms, A., et al. (2009). Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics. Neurobiol. Dis. 34, 107-112. Mamikonyan, E., Moberg, P.J., Siderowf, Duda, A. J., Have, T., Hurtig, H., Stern, M., Weintraub, D. (2009). Mild cognitive impairment is common in Parkinsons disease patients with normal MiniMental State Examination (MMSE) scores. Parkinsonism Relat. Disord. 15, 226-231.
imaging to visualize amyloid plaques in AD, is now being utilized to investigate related dementias. Several recent studies have demonstrated that PiB retention on PET, as a measure of amyloid burden, can both help distinguish DLB from PDD and predict overall cognitive dysfunction (Gomperts et al., 2008; Edison et al., 2008; Maetzler et al., 2009). DLB, PDD and AD share many clinical and pathologic features, but demand accurate diagnosis for appropriate management of the patient, which should soon be possible.
PARKINSONS DISEASE: ADVANCES IN MOlECUlAR NEUROPAThOlOGy

by Isidro Ferrer
For a long time, Parkinsons disease (PD) has been considered as neurodegenerative disease characterized by progressive loss of neurons of the substantia nigra pars compacta (SNpc), and clinically manifested by tremor, rigidity, gait disturbances and slowness appearing when loss of neurons in SNpc exceeds 60% of the total population. Remaining neurons have inclusions named Lewy bodies (LBs), composed of protein aggregates; the main component of which is abnormally phosphorylated, oxidized and nitrated -synuclein (-Syn) with altered solubility and conformation. Yet, recent studies have shown that loss of olfaction, gastrointestinal dysfunction, abnormal heart innervation, sleep disturbances and mood disorders may occur before the appearance of classical Parkinsonian symptoms. Moreover, impaired cognition, eventually leading to dementia, may occur in a high percentage of patients. Interestingly, clinical symptoms do not closely correlate with LBs suggesting that they are not causative, but rather a consequence of the illness. Genetic studies have demonstrated divergent pathogenic genes involved in familial, and sometimes sporadic PD including those encoding -Syn, parkin, PINK1, DJ1, LRRK2, UCHL1 and HtrA2 (Gasser, 2009). All post-mortem examinations show loss of neurons in SNpc, but certain parkin and LRRK2 mutations do not present with LBs. These observations indicate that PD is a multi-systemic disease affecting the central and vegetative nervous system. It may be caused by different genes; although, the majority of cases are probably due to environmental and genetic factors, and LBs are not essential components (Lees et al., 2009). Molecular neuropathology has revealed important clues in the pathogenesis of neurodegenerative diseases (Ferrer, 2009a). Crucial aspects are mitochondrial dysfunction, and
RefeRences
Ferrer, I. (2009a). Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimers disease. J. Bioenerg. Biomembr. [Epub ahead of print] PMID: 19798558. Ferrer, I. (2009b). Early involvement of the cerebral cortex in Parkinsons disease: convergence of multiple metabolic defects. Prog. Neurobiol. 88, 89-103. Gasser, T. (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev. Mol. Med. 11, e22. Lees, A. J., Hardy, J., and Revesz, T. (2009). Parkinsons disease. Lancet 373, 2055-2066. Navarro, A., Boveris, A., Bndez, M. J., Sanchez-Pino, M. J., Gomez, C., Muntane, G., and Ferrer, I. (2009). Human brain cortex: mitochondrial oxidative damage and adaptive response in Parkinson disease and in dementia with Lewy bodies. Free Radic. Biol. Med. 46, 1574-1580.
increased production of reactive oxygen species leading to oxidative damage to DNA, RNA, lipids and proteins that may affect energy production (Navarro et al., 2009). This is further complicated by abnormal lipid composition of membranes, which in turn increase energy demands. This scenario probably results in neuronal exhaustion. Since neurons are social cells that depend on trophic factors and synaptic inputs, and interact with glial cells particularly
isidro ferrer graduated from the University of Barcelona Medical School in 1973. He received his doctorate in Medicine from the University of Barcelona and specialized in pathology. He is currently Full Professor of Pathology and Neuropathology at the University of Barcelona, and Director of the Institute of Neuropathology at the IDIBELL-University Hospital Bellvitge in Hospitalet de Llobregat, Barcelona. He has produced about 500 international papers and book chapters focused on different aspects of human and animal neuropathology. 8082ifa@gmail.com
astrocytes an imbalance between internal homeostasis and external signals may explain fluctuations and day-to-day variations in PD and related disorders (Ferrer, 2009b). Functional neuroimaging studies underway show wide areas of impaired metabolism in the cerebral cortex in PD cases that confirm molecular observations. It may be proposed that internal mitochondrial consumption is a putative cause of cell death mediated by the mitochondrial pathway of apoptosis. Additional causes of cell death may be related to endoplasmic reticulum stress, impaired autophagy and necrosis. These observations show that harmful molecular dysfunctions occur before the appearance of neuron loss, and point to the need for further work designed to increase understanding of the very early events that precede clinical symptoms in PD. Although the search for a cure for PD is still appropriate, new strategies geared to delay the onset or to prevent the development of PD are in order.
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RefeRences
AMyOTROPhIC lATERAl SClEROSIS

by Orla hardiman
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative syndrome characterized by loss of upper and lower motor neurons. Cognitive impairment occurs in a significant proportion of those affected, indicating that neurodegeneration also occurs in regions outside the motor system (Phukan et al., 2007). The worldwide frequency of ALS is not known. In Europeans, the incidence is approximately 2/100,000 and the prevalence 6/100,000, with a slight male predominance (Cronin et al., 2007). The frequency of ALS is lower in those of mixed ancestral origin (Cronin et al., 2007). Life expectancy is 3-5 years from date of first symptom, although 10% of those affected can live for longer than 8 years. 5% of ALS is familial, and up to 12 genes and loci have been identified to date (Beleza-Meireles and Al-Chalabi, 2009). The pathogenesis of ALS is not well understood. It is thought to be a complex genetic disease, in which genetic susceptibility to neurodegeneration interacts with environmental exposures. The most widely used animal model of ALS is the SOD1 transgenic mouse. No definitive consensus has emerged as to how SOD1 mutations lead to premature death of motor neurons. Various pathways have been implicated including protein misfolding, altered mitochondrial function, the development of axonal transport defects, and the excessive production of extracellular superoxide radicals and the activation of stress pathways within the endoplasmic reticulum. The validity of the SOD1 transgenic mouse as a reliable model of human ALS has been undermined by the recent observation that neurons from mSOD1 mice do not exhibit mislocalized C-terminal tar DNA binding protein P-43 (TDP-43) fragments or hyperphosphorylated cytosolic TDP-43, as is the case in almost all human ALS. New techniques in molecular and cell biology have provided insights into the factors that increase disease susceptibility in human ALS. A number of susceptibility genes have been identified, including SMN, HFE and the paroxonase complex, although the precise mechanism by which neuronal injury, glial activation, and neuronal death occur remain to be fully elucidated (Beleza-Meireles and
orla Hardiman is a Neurologist and Clinician Scientist at Trinity College & Beaumont Hospital Dublin, Ireland. She is a specialist in ALS and related conditions, and an expert in epidemiology, genetic epidemiology, clinical neurological phenotyping, genotype-phenotype correlations, and translational research in ALS. orla@hardiman.net
Andersen, P. M., Borasio, G. D., Dengler, R., Hardiman, O., Kollewe, K., Leigh, P. N., Pradat, P. F., Silani, V., and Tomik, B. (2007). Good practice in the management of myotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group. Amyotroph. Lateral Scler. 8, 195-213. Beleza-Meireles, A., and Al-Chalabi, A. (2009). Genetic studies of amyotrophic lateral sclerosis: controversies and perspectives. Amyotroph. Lateral Scler. 10, 1-14. Cronin, S., Hardiman, O., and Traynor, B. J. (2007). Ethnic variation in the incidence of ALS: a systematic review. Neurology 68, 1002-1007. Lanka, V., and Cudkowicz, M. (2008). Therapy development for ALS: lessons learned and path forward. Amyotroph. Lateral Scler. 9, 131-140. Phukan, J., Pender, N. P., and Hardiman, O. (2007). Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 6, 994-1003.
Al-Chalabi, 2009). The recent discovery of a number of important genes associated with RNA processing, including TDP-43, FUS and ANG, opened a new field of research in ALS centering on RNA regulation. There is no cure for ALS. At present, there is only one effective disease modifying drug (riluzole), which improves survival by up to three months in most studies. Although riluzole is anti-glutamatergic, the mechanism of action in ALS remains unclear. Clinical biomarkers of disease onset and progression are urgently required to support the development of novel therapeutics. Despite the absence of a cure, good clinical management improves both quality of life and survival (Andersen et al., 2007). Attendance at a specialist multidisciplinary clinic improves survival by 6-9 months. Introduction of symptomatic management, including non-invasive ventilation, can confer a survival benefit of up to 9 months. New therapies are urgently required, but lessons must be learned from the failures of previous clinical trials (Lanka and Cudkowicz, 2008). Effective translation from pre-clinical to clinical studies will require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue.
CURRENT OUTlOOK ON hUNTINGTONS DISEASE

by Mark E. hester, Mathew J. Murtha and brian K. Kaspar
Huntingtons disease (HD) is an incurable, autosomal dominant, neurodegenerative disease encompassing multiple symptoms including behavioral, cognitive, and motor deficits. HD is named after George Huntington, who first described the disease as a genetic movement disorder in 1872. 121 years later, alterations in the number of CAG tri-nucleotide repeats at the beginning of the huntingtin gene (HTT) were deemed responsible for causing this debilitating disease. Typically, people with 36 or greater CAG repeats are at risk for developing the disease; greater numbers of repeats correlate to earlier time of onset and increased severity. These DNA repeats result in the expansion of polyglutamine tracts within the protein leading to preferential toxicity to striatal medium spinal neurons (Walker, 2007).
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Mark e. Hester, Ph.D., is a Post-doctoral Fellow in the laboratory of Dr. Brian Kaspar at the Research Institute at Nationwide Childrens Hospital in Columbus, Ohio. He obtained his doctorate degree in the Department of Molecular Genetics at The Ohio State University in 2005. His research focuses on developing strategies to increase differentiation efficiencies of adult and pluripotent stem cells to CNS specific cell types including motor neurons as a source to model neurodegenerative diseases such as Lou Gehrigs disease. mark.hester@nationwidechildrens.org
RefeRences
Cicchetti, F., Saporta, S., Hauser, R. A., Parent, M., Saint-Pierre, M., Sanberg, P. R., Li, X. J., Parker, J. R., Chu, Y., Mufson, E. J., et al. (2009). Neural transplants in patients with Huntingtons disease undergo disease-like neuronal degeneration. Proc. Natl. Acad. Sci. USA 106, 12483-12488. Harper, S. Q. (2009). Progress and challenges in RNA interference therapy for Huntington disease. Arch. Neurol. 66, 933-938. Harper, S. Q., Staber, P. D., He, X., Eliason, S. L., Martins, I. H., Mao, Q., Yang, L., Kotin, R. M., Paulson, H. L., and Davidson, B. L. (2005). RNA interference improves motor and neuropathological abnormalities in a Huntingtons disease mouse model. Proc. Natl. Acad. Sci. USA 102, 5820-5825. Shin, J. Y., Fang, Z. H., Yu, Z. X., Wang, C. E., Li, S. H., and Li, X. J. (2005). Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001-1012. Subramaniam, S., Sixt, K. M., Barrow, R., and Snyder, S. H. (2009). Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327-1330. Walker, F. O. (2007). Huntingtons disease. Lancet 369, 218-228.
The mechanism by which ubiquitous mutant huntingtin confers specific toxicity to cortical and striatal neurons remains obscure. Recent evidence has suggested that mutant huntingtin causes glial dysfunction (Shin et al., 2005), implicating both cell and non-cell autonomous mechanisms in the pathogenesis of HD. However, an important recent study suggests a protein called Rhes, which is highly expressed in the corpus striatum where neuropathology occurs, accounts for the selectivity of neuropathology (Subramaniam et al., 2009). Rhes directly interacts with HTT and subsequently adds a small protein called SUMO to HTT converting it from an insoluble aggregate to a soluble toxic form. This is now thought to cause selective neuronal cell death within the striatum. Future experiments are underway to determine whether removing Rhes from a HD mouse model would provide neuroprotection within the striatum. In addition, drugs that block the interaction between Rhes and mutant huntingtin could prove to be a viable treatment option. Alternative potential treatment options for HD include cell based therapies, which rely on stem cells or neural transplant grafts to replace diseased or dying neurons. Recently, a study was published documenting the clinical evaluation of a
neural transplantation that was administered to the caudate and putamen of HD patients 10 years ago (Cicchetti et al., 2009). In two patients, several putamen grafts survived, although disappointingly these patients also exhibited severe brain atrophy similar to age-matched control patients. Several factors may have contributed to the graft degeneration including lack of trophic support, excitotoxicity, and microglial activation; all of which are of current and future studies (Cicchetti et al., 2009). Although there are multiple targets for the development of HD therapies, the target with the most potential is the mutant huntingtin protein itself. RNA interference (RNAi) therapy has emerged as the most promising treatment option by directly
decreasing mutant gene expression. Indeed, the first published pre-clinical study showed that delivery of a shRNA to HTT by an AAV1 viral vector significantly restored rotorod performance and ameliorated gait dysfunction in an HD mouse model (Harper et al., 2005). Challenges for RNAi therapy for HD include off-target effects and safety risks associated with reducing normal HTT gene expression (Harper, 2009). Recent advances in the molecular biology underlying Huntingtons disease will provide new therapeutic targets. These new targets, in addition to the dozens of potential compounds and therapies already in the clinical pipeline for HD, provide a promising outlook for the potential to treat this debilitating disease.
Mathew J. Murtha is a Senior Graduate Research Associate performing his dissertation research in the laboratory of Dr. Brian Kaspar at the Research Institute at Nationwide Childrens Hospital in Columbus, Ohio, as part of the Molecular, Cellular and Developmental Biology graduate program at The Ohio State University. His research is focused on the directed differentiation of embryonic stem cells to specific neuronal subtypes of the spinal cord. mathew.murtha@nationwidechildrens.org
brian K. Kaspar, Ph.D., is Assistant Professor of Pediatrics and Principal Investigator at The Ohio State University and The Research Institute at Nationwide Childrens Hospital in Columbus, Ohio. Dr. Kaspars laboratory focuses on gene therapy and stem cell biology studies to model and develop therapies toward neurodegenerative diseases. The laboratory focuses on basic research in neurodegeneration with an emphasis on translational-based studies. brian.kaspar@nationwidechildrens.org
ChOlESTEROl AND AlZhEIMERS DISEASE

by Othman Ghribi
The finding by Corder et al. in 1993 that the 4 allele of the lipoprotein E (ApoE) gene is associated with a high risk for late-onset Alzheimers disease (AD) put cholesterol on the front stage as a potential risk factor for AD. Not only is ApoE tightly linked to cholesterol transport, it also closely interacts with -amyloid (A) overproduction of which is a pathological hallmark of AD. Indeed, ApoE is a major transporter of both peripheral and brain cholesterol, localizes in amyloid plaques, regulates deposition and clearance of A, and is associated with high plasma cholesterol. The discovery by Larry Sparks (1994) that high cholesterol diet-fed rabbits, a model system of coronary heart disease, exhibit cerebral A plaques reinforced the cholesterol-AD link hypothesis. Increased A production has also been shown in transgenic animal models of AD that were fed cholesterolenriched diets, and in cells incubated with cholesterol. Additionally, processing of the
A precursor protein by BACE1 yielding A, is known to be enhanced by a cholesterol-rich environment. However, because the brain makes its own cholesterol independent of the plasma cholesterol pool it is difficult to understand how plasma cholesterol contributes to A plaque build-up in the brain. More importantly, plasma cholesterol levels do not appear to correlate with progression of dementia in humans with AD patients having either normal, low or high plasma cholesterol levels. Two recent reports make it clear that cholesterol is linked to AD pathogenesis. An epidemiological study has demonstrated that high cholesterol levels during mid-life are associated with a 66% increase in AD risk late in life (Solomon et al., 2009). These findings suggest that the plasma cholesterol level in our 40s may determine our degree of risk for AD. At later age, when AD progresses, the correlation between AD and cholesterol levels is no longer consist-
othman ghribi obtained his Ph.D. in Pharmacology from the University of Rene Descartes, Paris, France. He completed post-doctoral training at the University of Quebec and at the University of Virginia. Dr. Ghribi joined the University of North Dakota, School of Medicine and Health Sciences, in 2004 as an Assistant Professor. His research interests include understanding the extent to which and the mechanisms by which environmental and dietary factors may contribute to the pathogenesis of Alzheimers disease. oghribi@medicine.nodak.edu
High plasma cholesterol
Increased levels of oxysterols
Blood brain barrier leakage
Increased entrance into the brain of neurotoxins and oxysterols
Impairment of cholesterol distribution and clearance
Accumulation of cholesterol in neurons
Increased APP processing by BACE Increased production of A Decreased clearance of A
A plaques
figure 1. Potential mechanisms that link cholesterol to A production.
ent. Two genome-wide association studies have established clusterin as a new genetic risk factor for late-onset AD (Harold et al., 2009; Lambert et al., 2009). What links clusterin to cholesterol and A is that clusterin, like ApoE, is an abundantly expressed lipoprotein in the brain that promotes the aggregation of A and localizes in amyloid plaques. When working in concert with ApoE, the clusterin-ApoE duo can foster A clearance and prevent the aggregation of this peptide.
These recent studies, together with previous data, suggest that cholesterol metabolism is linked to the pathogenesis of AD. However, the question as to how the plasma cholesterol pool contributes to the generation of AD pathologies in the brain remains to be answered. One possible mechanism is that oxidized cholesterol metabolites (oxysterols) can cross in and out of the brain (Bjrkhem et al., 2009) and may represent the dangerous liaison between cholesterol and the onset of AD. It may also be possible that hypercholesterolemia compromises the blood brain barrier, allowing entrance of neurotoxins into the brain and disturbing cholesterol distribution and clearance. Such a scenario may lead to dysregulation in ApoE function, accumulation of cholesterol in neurons, increased A production, impaired clearance of this peptide, and formation of A plaques (Figure 1).
RefeRences
Bjrkhem, I., Cedazo-Minguez, A., Leoni, V., and Meaney, S. (2009). Oxysterols and neurodegenerative diseases. Mol. Aspects Med. 3, 171-179. Harold, D., Abraham, R, Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimers disease. Nat. Genet. 41, 1088-1093. Lambert, J. C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., Tavernier, B., et al. (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimers disease. Nat Genet. 41, 1094-1099. Solomon, A., Kivipelto, M., Wolozin, B., Zhou, J., and Whitmer, R. A. (2009). Midlife serum cholesterol and increased risk of Alzheimers and vascular dementia three decades later. Dement. Geriatr. Cogn. Disord. 28, 75-80. Sparks, D. L., Scheff, S. W., Hunsaker, J. C. 3rd, Liu, H., Landers, T., and Gross, D. R. (1994). Induction of Alzheimer-like -amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp. Neurol. 126, 88-94.
AlZhEIMERS DISEASE GOES TAU

by Khalid Iqbal
Alzheimers disease (AD) is multifactorial and is caused by several different etiopathogenic mechanisms. Independent of the etiology, this disease is characterized clinically by chronic and progressive dementia and histopathologically by neurofibrillary degeneration of abnormally hyperphosphorylated tau seen as intraneuronal neurofibrillary tangles, neuropil threads and dystrophic neurites, and by neuritic (senile) plaques of -amyloid (GrundkeIqbal et al., 1986). The neurofibrillary degeneration is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau also promotes its selfassembly into tangles of paired helical and/or straight filaments (Alonso et al., 2006). Tau is phosphorylated by a number of enzymes called protein kinases. The specific tau protein kinases, which have been most implicated and are therapeutic targets for AD, include glycogen synthase kinase 3, cyclin-dependent protein kinase 5, calcium calmodulin-dependent protein kinase II, and protein kinase A. Among the enzymes that dephosphorylate phosphoproteins, the enzyme protein phosphatase-2A (PP2A) is the major tau phosphatase (Iqbal et al., 2009). The activity of PP2A, which is down-regulated in AD brain and is suspected to be a cause of abnormal hyperphosphorylation of tau, is negatively regulated by two intracellular proteins called I1PP2A and I2PP2A. These two inhibitors of PP2A are up-regulated and are believed to be a cause of the decreased PP2A activity and of abnormal hyperphosphorylation of tau in AD brain. In the case of I2PP2A, this protein is selectively cleaved
Khalid iqbal is Professor and Chairman of Neurochemistry at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York. Dr. Iqbals pioneering studies on neuronal protein pathology and discoveries of tau protein and its abnormal hyperphosphorylation in Alzheimers disease has won him many prestigious honors and awards, including the Potamkin Prize for Alzheimers Disease Research, American Academy of Neurology, and Zenith Award, Alzheimers Association. Dr. Iqbal was the Founder/Chairman of ICAD from 19882007. khalid.iqbal.ibr@gmail.com
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RefeRences
Alonso, A. D., Li, B., Grundke-Iqbal, I., and Iqbal, K. (2006). Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl. Acad. Sci. USA 23, 88648869. Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., and Binder, L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83, 4913-4917. Iqbal, K., Flory, M., Khatoon, S., Soininen, H., Pirttila, T., Lehtovirta, M., Alafuzoff, I., Blennow, K., Andreasen, N., Vanmechelen, E., and Grundke-Iqbal, I. (2005). Subgroups of Alzheimers disease based on cerebrospinal fluid molecular markers. Ann. Neurol. 58, 748-757. Iqbal, K., Liu, F., Gong, C. X., Alonso Adel, C., and Grundke-Iqbal, I. (2009). Mechanisms of tau-induced neurodegeneration. Acta Neuropathol. 118, 53-69. Tanimukai, H., Grundke-Iqbal, I., and Iqbal, K. (2005). Up-regulation of inhibitors of protein phosphatase-2A in Alzheimers disease. Am. J. Pathol. 166, 1761-1771.
into two fragments and translocated from the neuronal nucleus to the cytoplasm where it probably causes neurofibrillary degeneration (Tanimukai et al., 2005). These studies suggest a novel etiopathogenic mechanism of AD, which is initiated by the cleavage of I2PP2A, thereby inhibiting PP2A, which increases abnormal hyperphosphorylation of tau, and consequently leading to neurodegeneration. The inhibition of abnormal hyperphosphorylation of tau is one of the most promising therapeutic targets for the development of disease modifying drugs. The abnormal hyperphosphorylation of tau can be inhibited 1) by inhibiting the activities of one or more tau protein kinases, the enzymes that phosphorylate tau; and 2) by increasing the activity of PP2A, the major tau phosphatase. The increase in
PP2A activity can be achieved by inhibiting the cleavage and activity of I2PP2A, a PP2A inhibitor. A great advantage of inhibiting neurofibrillary degeneration is that it can be monitored by evaluating the levels of total tau and tau phosphorylated at various known abnormally hyperphosphorylated sites in the cerebrospinal fluid of patients, obtained by lumbar puncture. There are at least five subgroups of AD, each is probably caused by a different etiopathogenic mechanism (Iqbal et al., 2005). The AD subgroup identification of patients can help increase the success of clinical trials and the development of specific and potent disease modifying drugs. In summary, tau is pivotally involved in the etiopathogenesis and is one of the most promising targets, both for molecular diagnostics and therapeutics of AD.
SECRETASES AND AlZhEIMERS DISEASE

by Kumar Sambamurti
The pathology of Alzheimers disease (AD) is complex and consists of neurodegeneration, synaptic loss, neurofibrillary tangles and senile plaques containing deposits of the -amyloid protein (A) of 42 residues (A42) (Sambamurti et al., 2006). Most familial AD (FAD) mutations increase the levels of A42, linking it to the cause of AD (Sambamurti et al., 2006). The A sequence spans portions of the ectodomain and transmembrane domains of a larger (695-770 aa) type-I integral membrane A protein precursor (APP). As shown in Figure 1, most APP is cleaved between residues 16 and 17 of A by -secretase (multiple proteases of the adamalysin family), to a secreted derivative termed sAPP and a membrane-bound C-terminal fragment (CTF) of 83 aa (CTF)(Sambamurti et al., 2006). However, some APP (~10%) is cleaved by -secretase (identified as BACE-1) to a CTF of 99 residues (CTF), which is processed by -secretase: initially to A48/9, sequentially to smaller memKumar sambamurti, Ph.D., has studied AD for the last 20 years. His major contributions have been in understanding the regulation of the proteolytic processing of APP. His major contributions to the field started with the characterization of the cell biology of APP processing in intracellular compartments. Eight years after the discovery of A, his lab developed a -secretase assay and detected large quantities of the intracellular fragment of APP, which has facilitated the understanding of intramembrane proteolysis. sambak@musc.edu
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Diseased brain tissue from an Alzheimers patient showing senile plaques located in the gray matter of the brain; 1000x magnification. sAPP sAPP
P3
A49
A40/42
P3
MeMbrAne
CTF
APP
CTF
CTF/AICD
> 90 %
< 10 %
figure 1. Pathways of APP processing. The schematic diagram shows that APP is cleaved by either - secretase (green pacman) or -secretase (red pacman) to secrete large ectodomain derived fragments named sAPP /. The -secretase pathway bisects A into two fragments that are believed to be nontoxic, but the relatively minor secretase pathway generates CTF, which is subsequently processed by -secretase at the site to generate A49 and CTF (aka AICD) of 50 residues. Further sequential 3-4-residue cleavage of A49 generates A40/42.
brane-bound fragments (A45/6), and ultimately to A40 and to a lesser extent to A42 (Xu, 2009). A complex of four essential subunits named presenilin (PS1, PS2), nicastrin (NCT), Aph1 (a, b) and Pen2 form the active -secretase (Sambamurti et al., 2006). FAD mutations have not been detected on BACE-1, but its levels are increased around senile plaques. However, one FAD mutant APP670NL is a superior BACE-1 substrate, supporting its importance in AD pathogenesis (Sambamurti et al., 2006). Recent studies suggest that cathepsin-B processes at least a pool of wild type APP like BACE-1, but does not cleave the 670NL variant (Hook et al., 2008). However, cathepsin-B has also been identified as an A-degrading enzyme that exacerbates amyloid pathology in mice expressing APP670NL (Mueller-Steiner et al., 2006), suggesting that its role in AD pathogenesis is complex as it can both foster and inhibit A.
In contrast to BACE-1, most FAD mutations are linked to PS1 and PS2 subunits of -secretase (Sambamurti et al., 2006). Most PS1/2 and APP mutations do not affect -secretase processing, but subtly increase the ratio of A42/A40. Recent studies show that high isoprenoid levels modulate -secretase to increase A42/A40 and, therefore, phenocopy FAD mutations (Zhou et al., 2008). This finding suggests that diet and other environmental factors may play a large role in AD pathogenesis and deserve the same scrutiny as genetics. The complex secretory proteolytic processing of APP summarized above is highly conserved and may serve as a general paradigm for membrane protein homeostasis, regulation and interactions, and its failure may influence multiple degenerative diseases. Acknowledgments These studies were supported by NIA grant # AG 023055. I thank Dr. Lucy Feingold for useful comments.
RefeRences
Hook, V. Y., Kindy, M., and Hook, G. (2008). Inhibitors of cathepsin B improve memory and reduce -amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J. Biol. Chem. 283, 7745-7753. Mueller-Steiner, S., Zhou, Y., Arai, H., Roberson, E. D., Sun, B., Chen, J., Wang, X., Yu, G., Esposito, L., Mucke, L., and Gan, L. (2006). Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimers disease. Neuron 51, 703-714. Sambamurti, K., Suram, A., Venugopal, C., Prakasam, A., Zhou, Y., Lahiri, D. K., and Greig, N. H. (2006). A partial failure of membrane protein turnover may cause Alzheimers disease: a new hypothesis. Curr. Alzheimer Res. 3, 81-90. Xu, X. (2009). Gamma-secretase catalyzes sequential cleavages of the AbetaPP transmembrane domain. J. Alzheimers Dis. 16, 211-224. Zhou, Y., Suram, A., Venugopal, C., Prakasam, A., Lin, S., Su, Y., Li, B., Paul, S. M., and Sambamurti, K. (2008). Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of Abeta and APP-CTFgamma. FASEB J. 22, 47-54.
MITOChONDRIAl OXyGEN TOXICITy IN AlZhEIMERS DISEASE

by Ana lloret and Jose Via
-amyloid peptide enters neurons Experimental evidence shows that the -amyloid (A) peptide enters neurons and causes damage inside the cells. Experiments by the group of George Perry and Mark Smith led to the conclusion that extracellular amyloid deposits could be protective (Moreira et al., 2006a). Amyloidogenic processing of amyloid precursor protein (APP) involves the sequential cleavages by -secretase and -secretase. The 99 amino acid C-terminal fragment of APP can be internalized and further processed by -secretase to produce A toxic fragments. Experiments performed in Oliveiras laboratory in Coimbra showed that A affects mitochondrial respiration leading to increased formation of oxygen radicals (Moreira et al., 2006b). Alterations in calcium homeostasis are significant in the pathophysiology of the internal damage caused by A. -amyloid peptide causes loss of respiratory chain function A peptide causes a loss of mitochondrial function and it does not cause toxicity in cells depleted of mitochondria Therefore, mitochondria are a requirement for the intercellular toxicity of the A peptide. We found that A increases production of reactive oxygen species. This is due to the loss of respiratory function because A interferes with heme by sequestering iron; thus, rendering the heme complexes inactive (Lloret et al., 2008). This interferes with the respiratory chain complexes leads to an increased production of reactive oxygen species, and hence to oxidative stress.
Ana lloret received her Ph.D. from the University of Valencia in 2000. She is now a Teaching Assistant at the Department of Physiology in the Medical School of Valencia. Dr. Llorets research interests are free radicals and antioxidants in Alzheimers disease. Dr. Lloret has directed two doctoral theses, has attended 40 international congresses, and she has published 30 scientific articles. ana.lloret@uv.es
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RefeRences
Lloret, A., Bada, M. C., Mora, N. J., Ortega, A., Pallard, F. V., Alonso, M. D., Atamna, H., and Via, J. (2008). Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimers disease. Free Radic. Biol. Med. 44, 20192025. Moreira, P. I., Cardoso, S. M., Santos, M. S., and Oliveira, C. R. (2006b). The key role of mitochondria in Alzheimers disease. J. Alzheimers Dis. 9, 101110. Moreira, P. I., Zhu, X., Liu, Q., Honda, K., Siedlak, S. L., Harris, P. L., Smith, M. A., and Perry, G. (2006a). Compensatory responses induced by oxidative stress in Alzheimer disease. Biol Res. 39, 7-13. Valls, S. L., Borrs, C., Gambini, J., Furriol, J., Ortega, A., Sastre, J., Pallard, F. V., and Via, J. (2008). Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell 7, 112-118. Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., and Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimers pathology in female mouse model of Alzheimers disease. Proc. Natl. Acad. Sci. USA 106, 14670-14675.
Both the production of oxidants and the occurrence of A peptide fragments, which interfere with the mitochondrial machinery, may lead to a release of cytochrome C from
Jose via, received his Ph.D. from the University of Valencia in 1978 and was made full Professor of Physiology in 1986. Prof. Via is a member of numerous scientific societies and is editor of several scientific journals. Prof. Vias research interests are free radicals and antioxidants in exercise, aging and age-associated neurodegenerative diseases. Prof. Via has received eight national and international awards for research, he has directed 39 doctoral theses, attended 160 congresses as an invited speaker, and he has published over 200 scientific articles. jose.vina@uv.es
mitochondria. This activates the internal pathway of apoptosis providing a mechanistic insight into the apoptotic death of neurons Effect of gender in Alzheimers disease It is well established that Alzheimers disease (AD) occurs preferentially in women rather than men. Therefore, one could think that the A peptide is more toxic in the presence of estrogens. This is not the case. We have observed that mitochondria from females are protected against the toxic effects of A (Lloret et al., 2008). However, when A is incubated with brain mitochondria from older females, its toxic effects are more pronounced than in males. We postulate that the A peptide is more toxic in males than in
females, but that the situation is reversed in old age when estrogen activity decreases. The group of Brinton postulated that mitochondrial energetic deficit precedes the onset of AD in a female mouse model. The authors propose that this mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes the onset of full-blown AD and suggest possible therapeutic targets for its prevention (Yao et al., 2009). We found that genisteine protects against AD because it rescues neurons from A toxicity by inhibiting the activation of p38 (Valls et al., 2008). Thus, it is possible that treatment with estrogenic compounds may open a pathway to prevent, and perhaps even treat, the early stages of AD.
ANIMAl MODElS OF PARKINSONS DISEASE

by Michael K. lee
were essential for developing palliative therapies, use of these models has not led to successful disease modifying therapies for PD (Olanow et al., 2008). Since the toxin based model is not progressive and lacks the -Syn pathology, this model may not fully recapitulate the etiology of PD. However, chronic delivery of a dopaminergic toxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) has been shown to cause progressive loss of dopaminergic neurons and abnormal -Syn accumulation (Fornai et al., 2005). This model is important because it seems to connect the dots between dopaminergic toxins and the key neuropathologic features of PD: the loss of dopaminergic neurons and the -Syn pathology. In the future, it would be important to determine what neurodegenerative pathways are active in the chronic MPTP toxin model and determine how this model is mechanistically linked to genetic models of PD. The models of recessive PD are confusing, since loss of PD-related genes in drosophila leads to severe phenotypes, but the loss of these genes in mice leads to a very modest phenotype (Kitada et al., 2009). In contrast, sufficient expression of the autoMichael K. lee received his Ph.D. in Neuroscience from the University of Virginia in 1991. Following a Post-doctoral Fellowship at Johns Hopkins University, he became a faculty member at Johns Hopkins University in 1994. He is currently Professor of Neuroscience and Co-Director of the Center for Neurodegenerative and Neuromuscular Diseases, Institute for Translational Neuroscience, at the University of Minnesota. Dr. Lee is internationally recognized for his efforts in transgenic mouse modeling of neurodegenerative diseases (motor neuron diseases, Parkinsons disease, and Alzheimers disease). mklee@umn.edu
RefeRences
Animal models of a neurodegenerative disease are important because they provide insights into the early disease process and a platform for testing novel therapies. While genetic mutations cause a small subset of PD cases, causes for most PD cases are unknown (Lees et al., 2009). Thus, it has been difficult to effectively model PD in animals. Currently, PD models can be categorized into two major classes: the dopaminergic toxin models and the genetic models (Thomas and Beal, 2007). The toxin models are based on the assumption that oxidative stress/ mitochondrial deficits, as seen in human PD cases, are pathogenic factors in PD. The genetic models assume that PD caused by gene mutation is mechanistically linked to idiopathic PD. In this regard, it is important that autosomal dominant familial PD, caused by -synuclein (-Syn) and LRRK2 mutations, recapitulate -Syn and extranigral pathology that are also prevalent in idiopathic PD. In contrast, the pathology in autosomal recessive familial PD, caused by parkin, DJ-1, and PINK1 mutations, are generally restricted to the nigrostriatal system without the presence of the -Syn pathology. Many of the currently used models are outlined in recent reviews (e.g., Thomas and Beal, 2007). The dopaminergic toxin models reproduce the severe loss of dopaminergic neurons seen in PD. While the toxin models
Fornai, F., Schluter, O. M., Lenzi, P., Gesi, M., Ruffoli, R., Ferrucci, M., Lazzeri, G., Busceti, C. L., Pontarelli, F., Battaglia, et al. (2005). Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc. Natl. Acad. Sci. USA 102, 3413-3418. Kitada, T., Tong, Y., Gautier, C. A., and Shen, J. (2009). Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J. Neurochem. 111, 696-702. Lees, A. J., Hardy, J., and Revesz, T. (2009). Parkinsons disease. Lancet 373, 2055-2066. Li, Y., Liu, W., Oo, T. F., Wang, L., Tang, Y., Jackson-Lewis, V., Zhou, C., Geghman, K., Bogdanov, M., Przedborski, S., Beal, M. F., Burke, R. E., Li, C. (2009). Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinsons disease. Nat. Neurosci. 12, 826-828. Thomas, B., and Beal, M. F. (2007). Parkinsons disease. Hum. Mol. Genet. 16, R183-194.
somal dominant PD genes in animals led to progressive neurodegeneration (Thomas and Beal, 2007). Currently, many transgenic mouse models that express human -Syn exhibit progressive neurodegeneration and -Syn pathology. While direct expression of -Syn in dopaminergic neurons causes their progressive degeneration, the genetic rodent models with the pan-neuronal -Syn expression do not exhibit robust degeneration of dopaminergic neurons. A recent report showed that expression of mutant LRRK2 can lead to dopaminergic abnormalities without cell loss in mice (Li et al., 2009). Given that LRRK2 mutations act like a strong risk factor (Lees et al., 2009), it is possible that additional factor(s), such as increased -Syn expression, may be required for a full expression of PD-like pathology in mice. Overall, modeling of PD in animals has evolved to a point where we will be able to study how multiple molecular pathways intersect to produce PD-like pathology. These efforts will lead to a better mechanistic understanding of the pathology and new therapeutic targets.
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COMMON PAThOGENIC MEChANISMS OF AlZhEIMERS DISEASE AND CANCER

by hyoung-gon lee1, Xiongwei Zhu1, hyun-Pil lee1, Xinglong Wang1, Vladan bajic2, Gemma Casadesus3 and Mark A. Smith1
At face value, the pathogenic mechanisms for cancer uncontrolled cell proliferation and Alzheimers disease (AD) uncontrolled cell death would appear to be incongruous. However, ironically, accumulating evidence suggests that these two devastating diseases may, in fact, be more similar than previously recognized and share the same mechanistic origin, namely a dysregulation of the cell cycle machinery. A great deal of evidence suggests that neurons vulnerable to degeneration in AD emerge from their normal post-mitotic state phenotypically suggestive of cells that are cycling, rather than the normal terminally differentiated non-dividing state (Lee et al., 2009a). This raises the question of what happens to neurons in AD that leads to the re-expression of mitotic markers. If the cell cycle machinery functions properly, one would anticipate that a proliferation of neurons should occur. However, the outcome in AD is not neuronal proliferation, but rather cell death, suggesting a failure of mitosis. Indeed, while various mitotic markers are upregulated in vulnerable neurons in AD, no evidence of actual mitosis has ever been found, suggesting that these neurons are arrested at a point(s) prior to the actual event of cell division (Zhu et al., 2008). Recently, we experimentally determined that cell cycle re-entry of fully differentiated post-mitotic neurons in vivo can
1
cause neurodegeneration (Lee et al., 2009b). In fact, in transgenic mice the induction of cell cycle re-entry by c-Myc, a well-known oncogene that is also increased in the vulnerable neurons in AD, led to a number of pathogenic and behavioral correlates of AD, including neuronal cell loss and cognitive deficits. These findings indicate a causal role for cell cycle re-entry in neurodegeneration in AD. Therefore, akin to the pathogenic origin of cancer, the inappropriate control of the cell cycle may be a key pathogenic mechanism of AD. While it is unclear why cell cycle re-entry in neurons causes neurodegeneration (rather than proliferation), one possible explanation could be the cellular context. Neurons may be programmed to be permanently post-mitotic for good reason, as a safety control system to prevent them from proceeding to mitosis. Further systematic studies of how neurons respond to the induction of the cell cycle and the signal transduction mechanisms involved are clearly warranted to explore the mecha-
RefeRences
Lee, H.-G., Casadesus, G., Zhu, X., Castellani, R.J., McShea, A., Perry, G., Petersen, R. B., Bajic, V., and Smith, M. A. (2009a). Cell cycle reentry mediated neurodegeneration and its treatment role in the pathogenesis of Alzheimer disease. Neurochem. Int. 54, 84-88. Lee, H.-G., Casadesus, G., Nunomura, A., Zhu, X., Castellani, R. J., Richardson, S. L., Perry, G., Felsher, D. W., Petersen, R. B., and Smith., M.A. (2009b). The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am. J. Pathol. 174, 891-897. Snape, M., Lee, H.-G., Casadesus, G., and Smith, M. A. (2009). Cell cycle aberrations in Alzheimers disease: a novel therapeutic opportunity. Expert Rev. Neurotherapeutics 9, 1579-1580. Zhu, X., Siedlak, S. L., Wang, Y., Perry, G., Castellani, R. J., Cohen, M. L., and Smith, M. A. (2008). Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol. Appl. Neurobiol. 34, 457-465.
Department of Pathology, Case Western Reserve University, Cleveland, USA Institute of Biomedical Research, Galenika a.d., Belgrade, Serbia Department of Neurosciences, Case Western Reserve University, Cleveland, USA
Hyoung-gon lee received his Ph.D. from Case Western Reserve University in 2005. Dr. Lee joined the faculty of the Department of Pathology at Case Western Reserve University in 2007. Dr. Lee is the recipient of several awards including the International Junior Investigator Award from the International College of Geriatric Psychoneuropharmacology and the Young Investigator Award from the American Society for Neurochemistry. Dr. Lees research is mainly focused on the pathogenic mechanism of Alzheimers disease. hyoung-gon.lee@case.edu
nism of cell cycle-mediated neurodegeneration. Understanding such regulatory mechanisms may provide new therapeutic targets for AD. In addition, such knowledge could also be relevant to the development of novel therapies to treat cancer, since inducing similar regulatory systems in cancerous cells could lead to cell death rather than proliferation. In conclusion, we hypothesize that the reactivation of the cell cycle without complete cell division in neurons in AD does not only lead to the pathological hallmarks of disease, but also, ultimately, to cell death. As such, therapeutics targeting cell cycle entry and/or progression may be useful for the treatment of AD (Snape et al., 2009).
Jack c. de la torre, M.D., Ph.D., has held professorial appointments at the University of Chicago, Northwestern University, University of Ottawa and is presently Senior Scientist at the Sun Health Research Institute. He has authored more than 200 peer-reviewed articles and written or edited ten volumes on CNS pathology, seven of these volumes dealing with Alzheimers disease (AD). In 1993, he introduced the concept of AD as a vascular disorder with neurodegenerative consequences that culminated in the CATCH (critically-attained threshold of cerebral hypoperfusion) hypothesis of AD. This concept continues its profound impact on AD research. jcdelatorre@comcast.net
POSTUlATES TO hElP VAlIDATE A CAUSAl RElATIONShIP TO AlZhEIMERS DISEASE

by Jack C. de la Torre
Controversy over the cause of Alzheimers disease (AD) still rages a century after this dementia was first described. Like Kochs four postulates, which were designed to support a causal relationship between a specific microbe and an infectious disease, three assumptions (or postulates) are presented here to aid vertical thinking relevant to the hypothesized cause of AD. Since nothing can be deduced if nothing is assumed, the three postulates offered below should obey the following rules: 1. the trigger or cause of AD should precede AD; 2. the trigger or cause of AD should precede cognitive loss and histopathology associated with AD and these events should not be present in cognitively normal people; 3. modifying or blocking the suspected trigger or cause of AD should reverse, arrest, or prevent cognitve decline and histopathology associated with AD. To test the empirical value of these postulates, three examples are offered from the AD research literature where a cause for AD has been proposed: 1) loss of cholinergic neurons in the basal forebrain, or cholinergic hypothesis of AD; 2) accumulation and deposition of -amyloid (A) in the brain, or A hypothesis of AD; and 3) chronic brain hypoperfusion, or vascular hypothesis of AD. These examples are summarized in Table 1. A scan of the AD literature discloses anecdotal or no evidence for either the loss of cholinergic neurons or the accumulation of A in the brain as causing cognitive decline in humans. These pathological lesions can be found in other neurodegenerative disorders besides AD, and in cognitively normal individuals. In addition, no blocking agent, including cholinesterase inhibitors or anti-A therapy, is reported to prevent or reverse cog-
Hypothetical cause agent loss of cholinergic neurons A brain accumulation chronic brain hypoperfusion
table 1. Causes of AD proposed in the literature.
cognitive decline no evidence no evidence adequate evidence
blocking none none partial evidence
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US boxer Floyd Patterson died in 2006 at age 71. He had Alzheimers disease for about eight years.
nitive decline or histopathology associated with AD. Lastly, the failure of cholinesterase inhibitors, or drugs that lower A burden from the brain, to arrest cognitive decline prior to or during AD indicates that evidence-based interventions targeting these hypothetical causes of AD are absent. While a consistent presence exists between AD and the loss of cholinergic neurons or A accumulation in the brain, these co-morbid events lack clinical findings to support a cause-effect relationship to AD, and such an assumption must be considered a post-hoc fallacy. By contrast, chronic brain hypoperfusion (CBH) accompanied by vascular risk factors (VRF) in elderly subjects presents clinical evidence favoring a cause-effect relationship to cognitive impairment preceding AD (de la Torre, 2002). This conclusion is conditional and is based on clinical studies reporting the presence of CBH in cognitively normal
individuals who later develop cognitive decline prior to AD conversion (Kitagawa et al., 2009) independent of gray matter atrophy (Johnson et al., 2005). Moreover, mildly cognitive impaired individuals who convert to AD, but are tested pre-clinically for brain perfusion, show selective hypoperfusion in the hippocampus (Caffarra et al., 2008) and in the entorhinal cortex the earliest site pathologically compromised in AD. Limited findings suggest that partial blocking of CBH or VRF results in better cognitive function and slower cognitive decline in affected patients (Deschaintre et al., 2009). Reversing or preventing cognitive impairment by fully blocking CBH or its VRF has not been attempted. The three postulates presented here may serve to question or to help validate a proposed hypothetical cause-effect relationship to AD and could be a useful model for designing therapy aimed at the factual pathogenesis of this dementia.
RefeRences
Caffarra, P., Ghetti, C., Concari, L., and Venneri, A. (2008). Differential patterns of hypoperfusion in subtypes of mild cognitive impairment. Open Neuroimag. J. 2, 20-28. de la Torre, J. C. (2002). Alzheimers disease as a vascular disorder: Nosological evidence. Stroke 33, 1152-1162. Deschaintre, Y., Richard, F., Leys, D., and Pasquier, F. (2009). Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology 73, 674-680. Johnson, N. A., Jahng, G. H., Weiner, M. W., Miller, B. L., Chui, H. C., Jagust, W. J., GornoTempini, M. L., and Schuff, N. (2005). Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234, 851-859. Kitagawa, K., Oku, N., Kimura, Y., Yagita, Y., Sakaguchi, M., Hatazawa, J., and Sakoda, S. (2009). Relationship between cerebral blood flow and later cognitive decline in hypertensive patients with cerebral small vessel disease. Hypertens. Res. 32, 816-820.
NEW PIllS FOR AUGUSTE D ?

by Merc boada
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The German psychiatrist and neuropathologist Alois Alzheimer (1864-1915).
RefeRences
Aisen, P. S. (2005). The development of anti-amyloid therapy for Alzheimers disease: from secretase modulators to polymerisation inhibitors. CNS Drugs 19, 989-996. Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T., Barberger-Gateau, P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., et al. (2007). Research criteria for the diagnosis of Alzheimers disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734-746. Hardy, J. (2006). A hundred years of Alzheimers Disease Research. Neuron 52, 3-13. Knopman, D. S., DeKosky, S. T., Cummings, J. L., Chui, H., CoreyBloom, J., Relkin, N., Small, G. W., Miller, B., and Stevens, J. C. (2001). Practice parameter: diagnosis of dementia (an evidence based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 56,1143-1153. Summers, W. K., Majovsky, L. V., Marsh, G. M., Tachiki, K., and Kling, A. N. (1986). Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. New Engl. J. Med. 315, 1241-1245.
Alzheimers disease (AD) is a chronic, progressive neurodegenerative disorder in which normal thinking and memory are disrupted probably due to impaired or blocked transmission of complex messages among brain cells. The symptoms of AD are cognitive and psychiatric, and cause difficulties in performing daily life activities (Knopman et al., 2001; Dubois et al., 2007) From the time of Auguste D. (18501906), Alois Alzheimers case report on Nov 4, 1906, until 1986 (Summers et al., 1986), we had no effective therapy for the dementia. Now we are limited to cholinesterase inhibitors and Ca2+-channel blockers; both affect the symptoms but not the disease. The principal characteristics in the neuropathology of AD are the formation of extracellular senile plaques containing fibrillar aggregates of an -amyloid pepMerc boada is a Neurologist and Ph.D. from the UAB. She is CMO at Fundaci ACE and Chief of the Dementia Unit at Hospital Vall dHebron in Barcelona. She focuses her research on genome and phenome of common diseases, biomarkers and neuroimaging for prodromic AD, and new treatment approaches. Her research has been funded by grants from EU and Spanish administration. She leads the Documento Sitges concerning protection for people with dementia. She received the 2008 Professional Excellence Award from the Medical Council of Catalonia. mboada@fundacioace.com
tide (A), and intracellular neurofibrillary tangles composed of a hyperphosphorylated tau protein. A causal role of A is supported by genetic studies and molecular data, showing aggregates, particularly in the form of oligomeric assembly intermediates. The amyloid cascade hypothesis is one of the several hypotheses that are used to explain the pathogenesis of AD, but it seems not to be the only one. Three basic science research tracks were pursued in order to improve understanding of the disease. The first, the neurochemical approach, has led to the currently available therapies. The second approach focused on the potential mechanism of A toxicity, while the third track aimed to identify the causative genes involved in the pathogenesis of early-onset Alzheimers disease (EOAD) and late-onset Alzheimers disease (LOAD). Clinical trials: new strategies for AD New clinical trials have been aimed at two main targets: first, at the early stage disease; and secondly, at the development of novel drugs to modify A production, avoid A aggregates, and achieve A clearance (Aisen, 2005). The main pharmacological targets are detailed in the following lines of research. Activation of -secretase: focusing on amyloid precursor protein (APP) processing through the neuroprotective, non-amyloidogenic pathway seems to be a logical alternative strategy. However, the
study of statins as -secretase regulators did not lead to any effective treatment. Inhibition/modulation of -secretase: focused on -secretase inhibitors and modulators capable of reducing the formation of pathogenic A. Interfering with A aggregation: compounds that inhibit A aggregation or disrupt the already formed amyloid plaque in brain tissue are under investigation. Immunotherapy with A-specific antibodies, which includes active or passive immunization, is thought to act through several mechanisms of action. A clearance: extracellular monomeric A can be cleared from the brain to the periphery, where it can be degraded or removed. RAGE (receptor for advanced glycation endproducts) is one potential target. Given that 90% of circulating A may be bound to albumin, the potential mobilization of plasma A bound to therapeutic albumin through plasma exchange is another new approach. Unfortunately, the answers to all these questions must await the results of the clinical trials until 2012 or thereafter. Since 1906, and echoing John Hardys article (Hardy, 2006), we have not gained any control over the disease scientists are in limbo. If Auguste D. was to celebrate her 160th birthday today, no new treatments would be found among her presents just a Happy Birthday to her.
Member of the Parkinsons Dance class at The Mark Morris Dance Center in Brooklyn, USA.
WANTED: A NEUROPROTECTIVE AGENT IN PARKINSONS DISEASE

by D. James Surmeier and Tanya Simuni
Parkinsons disease (PD) is the second most common neurodegenerative disease. At present, it is estimated that over a million people in the US are afflicted with PD. Age is the primary risk factor; as the average life span increases, so will the number of people suffering from PD. The PD population in the US is projected to double by 2025 and to increase even more in regions of the world, such as China, where improvements in health care are more dramatically extending life span (Dorsey et al., 2007). The cardinal motor symptoms of the disease bradykinesia, rigidity and tremor are due to the death of dopamine producing cells in the substantia nigra pars compacta (SNpc). In the early stages of the disease, these symptoms are effectively treated by boosting dopamine production from the remaining neurons or by mimicking the release of dopamine with directly acting agonists. But these therapies do not slow or stop the inexorable progression of the disease. At present, nothing is proven to hold the disease at bay. This is not for lack of trying (Yacoubian and Standaert, 2009); several ideas have been tested. The foremost of these has been that mitochondrial oxidative stress and dysfunction is somehow a key step in the pathogenesis and there is good experimental and clinical support for this point of view. But, to date, the clinical trials aimed at mitigating oxidative stress have failed (vitamin E, deprenyl, rasagiline, inosine, coenzyme Q10, creatine). It is possible that the idea is correct, but the clinical trials have failed for other reasons, e.g., poor trial design or incorrect dosing, and there are large NIH sponsored studies underway re-examining creatine and coenzyme Q10. Another idea, with both experimental and clinical support, is that inflammation plays a role in
D. James surmeier graduated from the University of Washington in 1983. He currently is the Nathan Smith Davis Professor and Chair of the Department of Physiology in the Feinberg School of Medicine at Northwestern University in Chicago, Illinois. He is also the Director of the Morris K. Udall Parkinsons Disease Research Center of Excellence at Northwestern University. j-surmeier@northwestern.edu
tanya simuni graduated from Leningrad Medical School and did a neurology residency at Temple University in Philadelphia, Pennsylvania. She currently is an Associate Professor in the Department of Neurology in the Feinberg School of Medicine at Northwestern University. She is also Director of the Parkinsons Disease and Movement Disorders Center at Northwestern University. tsimuni@nmff.org
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RefeRences
Becker, C., Jick, S. S., and Meier, C. R. (2008). Use of antihypertensives and the risk of Parkinson disease. Neurology 70, 1438-1444. Chan, C. S., Guzman, J. N., Ilijic, E., Mercer, J. N., Rick, C., Tkatch, T., Meredith, G. E., and Surmeier, D. J. (2007). Rejuvenation protects neurons in mouse models of Parkinsons disease. Nature 447, 1081-1086. Dorsey, E. R., Constantinescu, R., Thompson, J. P., Biglan, K. M., Holloway, R. G., Kieburtz, K., Marshall, F. J., Ravina, B. M., Schifitto, G., Siderowf, A., et al. (2007). Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68, 384-386. Olanow, C. W., Rascol, O., Hauser, R., Feigin, P. D., Jankovic, J., Lang, A., Langston, W., Melamed, E., Poewe, W., Stocchi, F., and Tolosa, E. (2009). A double-blind, delayed-start trial of rasagiline in Parkinsons disease. N. Engl. J. Med. 361, 1268-1278. Ritz, B., Qian, L., Rhodes, S. L., Schernhammer, E., Olsen, J., and Friis, S. (in press). L-Type Calcium Channel blockers and Parkinsons Disease in Denmark. Annals Neurol. (in press). Yacoubian, T. A., and Standaert, D. G. (2009). Targets for neuroprotection in Parkinsons disease. Biochim. Biophys. Acta 1792, 676-87.
PD. However, minocycline failed in clinical trials, and the epidemiological support for a linkage between anti-inflammatory drug use and risk of PD has wavered. The idea that excitotoxicity is a factor was delivered a blow by the failure of the glutamate receptor antagonist riluzole in clinical trials. Attempts to provide generalized trophic support of dopaminergic neurons with factors like glial derived neurotopic factor have also failed. A recent study of the monoamine oxidase B inhibitor rasagiline reported a slowing of PD progression (Olanow et al., 2009). The study used delayed start design to separate symptomatic effects from putative disease modification. As exciting as this result seems, the effects were modest and not dose-dependent, providing reason for caution. There could be any number of technical reasons why the clinical trials in PD
have failed. However, it is also possible that they have failed because they have not been aimed at the right target. The bottom line is that we do not understand what causes PD and this makes it very difficult to design a rationale therapy to stop it. The panoply of genetic mouse models of rare familial forms of PD hold promise on this score, but PD unfolds over decades, making it difficult to study the disease in rodents that live for a couple of years. What we are left with is proposing mechanisms that should, in principle, have a similar slow progression or preferentially target particular organelles (e.g., mitochondria). Another strategy is to ask what is different about those neurons that succumb first to the disease, hoping that this will reveal a chink in the neuronal armor. The first stab at this strategy revealed that the most vulnerable neurons in PD the SNpc
dopaminergic neurons have an unusual physiological phenotype that leads to sustained elevation in cytosolic calcium concentration (Chan et al., 2007). Calcium is a metabolically expensive ion that elevates oxidative stress and could, over time, disrupt mitochondrial function and promote cell death. Epidemiological studies have shown that calcium channel antagonists that get across the blood-brain barrier are associated with reduced risk of PD (Becker et al., 2008; Ritz et al., in press). Tolerability trials with an FDA approved dihydropyridines (isradipine) are underway now, and a phase II-III neuroprotection trial should begin soon. So at this point, the quest for a neuroprotective agent in PD has not been successful. Nevertheless, every day brings new insights into the mechanisms underlying neurodegeneration, providing hope that soon the tide will turn.
bIOMARKERS OF NEURODEGENERATION ThAT WOUlD PlEASE A VAMPIRE

by Judith A. Potashkin
Alzheimers disease (AD) and Parkinsons disease (PD) are chronic progressive debilitating diseases. Most cases of AD and PD are idiopathic, suggesting environmental factors play a role in disease onset along with genetic risk factors. Unfortunately, by the time patients first present in the physicians office with pathological symptoms, irreversible brain damage has often occurred. In this regard, early detection of these disorders, ideally before the onset of symptoms, could improve disease management. Currently, there are very few fully validated early stage biomarkers for AD or PD available. Environmental factors play a key role in regulating many steps of gene expression including transcription, alternative splicing, RNA stability and translation. Posttranscriptional studies are extremely sparse in AD and PD research. This is surprising, considering that more than 95% of all transcripts are regulated by alternative splicing, the process that produces several mRNAs from a single pre-mRNA. MiRNAs act as a rheostat for gene expression mainly by destabilizing mRNAs and inhibiting translation. Estimates are not available for how great of a role miRNAs play in regulating gene expression; however, it is likely that they play a very large role. Recently, it has become clear that dysregulated pre-mRNA splicing and miRNA-mediated gene regulation may result in neurodegeneration (Figure 1). Therefore, it is surprising that most studies to date have failed to recognize the potential of splice variants and miRNAs as biomarkers for diagnosis and monitoring treatment of neurodegeneration. Cells can respond rapidly to environmental stressors, such as enhanced oxidant load (a common stressor in neurodegenerative disease), through changes in the regulation of splice site selection, thereby altering the concentration of splice variants produced. In addition, the amounts of individual miRNAs fluctuate in response to environmental conditions including oxidative stress. Therefore, identification of RNA biomarkers from an easily obtained minimally invasive source, such as whole blood, plasma and serum, would be ideal for monitoring an individual. In this regard, it is clear that the immune system responds to changes in neurotransmitters. Recently, a brain-to-T-cell pathway was proposed to explain how peripheral T lymphocytes might respond to dopamine in the brain based on the fact that T lymphoblast can cross the blood-brain barrier (Ilani et al., 2004). Support for the idea that changes in gene expression in blood cells reflect the development of neurodegenerative diseases comes from several recent reports (Scherzer et al., 2007; Gatta et al., 2009; Grnblatt et al., 2009). Unfortunately, potentially useful biomarkers for AD and PD may have been missed because these studies looked at total mRNA, instead of splice variant-specific mRNA and miRNAs. In biomarker studies, investigators have often used blood cells as the sole source of RNA, unaware of that RNAs in microvesicles are
Judith A. potashkin, Ph.D., is an Associate Professor of Cellular and Molecular Pharmacology at Rosalind Franklin University of Medicine and Science. She received her doctoral degree at State University of New York, Buffalo, and did her post-doctoral studies at Cold Spring Harbor Laboratory. Recently, Dr. Potashkin has focused her research involving RNA processing on understanding the molecular mechanisms of neurodegeneration. Dr. Potashkin currently receives support from the Department of Defense USAMRAA for these studies. judy.potashkin@rosalindfranklin.edu
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present in serum. In addition to these deficiencies, many technical barriers for preparing RNA from blood and identifying miRNAs and their target exist. Recently, studies from several labs, including ours, have begun to investigate RNAs as biomarkers of neurodegeneration in hope of eventually identifying biosignatures for AD and PD.
Healthy Genetically normal

SV1 SV2 miR-1 miR-2
Healthy environment
RefeRences
Gatta, L., Cardinale, A., Wannenes, F., Consoli, C., Armani, A., Molinari, F., Mammi, C., Stocchi, F., Torti, M., Rosano, G.M., et al. (2009). Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs. Neurosci. Lett. 453, 36-40. Grnblatt, E., Bartl, J., Zehetmayer, S., Ringel, T. M., Bauer, P., Riederer, P., and Jacob, C. P. (2009). Gene expression as peripheral biomarkers for sporadic Alzheimers disease. J. Alzheimers Dis. 16, 627-634. Ilani, T., Strous, R. D., and Fuchs, S. (2004). Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB J. 18, 1600-1602. Scherzer, C. R., Eklund, A. C., Morse, L. J., Liao, Z., Locascio, J. J., Fefer, D., Schwarzschild, M. A., Schlossmacher, M. G., Hauser, M. A., Vance, J. M., et al. (2007). Molecular markers of early Parkinsons disease based on gene expression in blood. Proc. Natl. Acad. Sci. USA 104, 955-960.
neurodegeneration Genetic vulnerability

SV1 miR-1 SV2 miR-2
Environmental stress
figure 1. The delicate balance. The upper panel depicts the proper balance of splice variants (SV) and miRNAs (miR) that is a result of inheriting a healthy genotype and living a healthy lifestyle. The bottom panel depicts an individual who has inherited genes that make the person more vulnerable to environmental stressors. In this individual, the balance of splice variants and miRNAs may become disrupted and eventually lead to neurodegenerative disease.
DRUG DISCOVERy IN NEURODEGENERATION MIND ThE GAP

by Adrian J. Ivinson
Most of the classic neurodegenerative diseases are disorders of the middle aged and elderly. As a consequence, any growth of the elderly demographic will result in a concomitant increase in neurodegenerative disease prevalence. For example, the US is seeing the first of the post WWII baby boomer generation entering their 60s and is also enjoying a steady increase in life expectancy. As a result, the US Alzheimers disease (AD) population will increase from approximately 5 million today to 16 million by 2050. That is, unless we collectively develop an effective way to either avoid, reverse or at least slow the disease with the introduction of disease modifying interventions most likely in the form of pharmaceutical drugs. To many newly diagnosed patients and their families, the fact that few such drugs exist for AD, Parkinsons disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntingtons disease and most other neurodegenerative diseases comes as a terrible shock. What they ask have university and hospital researchers and the biotechnology and pharmaceutical industry been doing all these years? What indeed! There is a pitifully small number of drugs to treat neurodegenerative diseases. To make matters worse, these drugs offer only symptomatic treatment as opposed to disease modification, and many are copycat drugs that bring nothing new to the clinic. This poor rate of new drug approvals has remained low over more than a decade, with just 12 new drugs meeting FDA approval in that period for all neurodegenerative diseases combined.
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biotech and pharma Academia
basic research
Drug Discovery
Drug Development
clinical trials
Approval
basic research
pathogenesis
target iD/val
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Ht screen
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figure 1. the neurodegenerative diseases drug discovery gap. The process for creating new drugs, from basic research through to regulatory approval, is weakest at the early drug discovery stage. Establishing non-profit biotech-style drug discovery groups within academia, that can assess the potential of new targets and advance the most promising of these through the preliminary steps that lead to more robust drug development programs, is a feasible and affordable approach to strengthening the currently weak drug pipeline.
clinical trials
Commentators have proposed several explanations for this sorry state of affairs: perhaps the nature of the central nervous system (CNS) makes discovering and developing drugs to treat brain disorders particularly challenging; chronic diseases, such as these, require very long and expensive clinical trials; current animal models of neurodegenerative diseases do not accurately predict success in human clinical trials; and compared to many other indications, neurodegenerative diseases present relatively small markets, and by extension a weaker economic argument for big pharmaceutical companies. We cannot change market forces, nor can we simplify the nature of the CNS. But there are other, more tractable, problems to address good progress is being made toward better mouse models and biomarkers that will make clinical trials faster and less expensive. There is another critical issue that we can immediately address. Drug discovery often emerges from a good understanding of disease mechanism and identification of a novel pathway or target research that generally takes place in an academic setting.
On the other hand, the costly and rigorous process of drug development is left to biotechnology and pharmaceutical companies. This division of labor has led to a significant cultural, financial and operational gap between two essential elements of the process (Figure 1). We can and should bridge this gap such that all potential disease targets emerging from academia are routinely assessed for their drug potential. It is perfectly feasible to create an environment physical and cultural that links the best of academias basic research to the focused and determined business of drug development. There are promising drug discovery ideas gathering dust on university shelves. The more of these we can assess and test in early stage drug discovery programs and then feed into the currently uninspiring pipeline for neurodegenerative disease drugs, the better the chances that collectively we will develop the disease modifying drugs that we need. Alternatively, our failure to bridge the academia-industry drug discovery gap will mean another generation of shocked patients who, upon receiving a devastating diagnosis, are offered little more than sympathy.
Adrian J. ivinson is the founding Director of the Harvard NeuroDiscovery Center a cross-institutional research center that translates knowledge of the structure and function of the brain into an understanding of the pathogenesis of major neurological diseases and therapeutic opportunities. Prior to this, he was the Editor-in-Chief of the journal Nature Medicine and Publisher of the Nature monthly journals. His interest in biomedical research extends to bioethics. adrian_ivinson@hms.harvard.edu
NEURODEGENERATIVE DISORDERS: GENE ThERAPy ON ClINICAl TRIAl

by Patrick Aebischer
Our molecular understanding of neurodegenerative diseases has made remarkable progress during the last decade. The genetic cause of diseases such as Huntingtons or spinal muscular atrophy has been unraveled. Numerous gene defects have been identified for the familial forms of amyotrophic lateral sclerosis, fronto-temporal dementia, Alzheimers and Parkinsons disease. In parallel, lentiviral viral vectors and adenoassociated vectors have been developed to the point that they can be safely considered for in vivo gene therapy clinical trials. Based on encouraging results obtained in primate models of Parkinsons disease (Jarraya et al., 2009), two clinical trials have been recently performed. The first one used equine infectious anemia virus (EIAV), a lentivirus, as a transfer vector for the striatal expression of key enzymes involved in the production of dopamine. The second one is based on the use of adeno-associated vectors type 2 for the striatal expression of neurturin, a dopaminergic trophic factor (Marks et al., 2008). Whereas these two approaches aim primarily at ameliorating the symptoms, no trial has attempted to correct the cause of the disease. Parkinsons disease constitutes an ideal case for gene therapy as its target, the substantia nigra pars compacta, is well defined and contains a small number of cells to be infected (less than one million dopaminergic nigral neurons). It remains to be elucidated which gene should be investigated for preventing neuronal demise. The first genes that come to mind are those involved in recessive forms of familial Parkinsons disease, namely parkin and
patrick Aebischer, M.D., is a Professor at the Brain Mind Institute of the Ecole Polytechnique Fdrale de Lausanne (EPFL) in Switzerland. Since 2000, he is also the President of EPFL, one of the Europes Premier Institutes of Technology. He is the founder of three biotechnology companies. His current research focuses on the development of gene transfer approaches for modeling and treating neurodegenerative diseases. He is also using emerging imaging techniques to develop biomarkers for neurodegenerative diseases. patrick.aebischer@epfl.ch
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RefeRences
pink1, whose overexpression may compensate for a loss of function. The small number of patients and the slow evolution of the disease question this approach. Whereas the down-regulation of -synuclein (-Syn) using RNAi technology seems a promising approach, the recent observation in rodents that -Syn silencing leads to a loss of nigral dopaminergic neurons in rodents has raised concerns about this strategy (Gorbatyuk et al., 2009). Other neurodegenerative diseases, such as Huntingtons or Alzheimers disease, will require infection of a large number of spread neurons a presently unresolved technical problem. The most promising diseases may paradoxically be those affecting motoneurons. Whereas Foust et al. (2009) have reported that the intravascular AAV-9 preferentially targets neonatal and adult astrocytes, Chris Towne in our laboratory has recently observed that the intrathecal injection of AAV-6 results in a very large number of motoneurons infected all along the spinal cord of rodents (Figure 1). Promising results have been observed in mouse models of spinal muscular atrophy by the overexpression of the smn gene. However, scale-up of the system to primates is required before moving to the clinic. Familial amyotrophic lateral sclerosis caused by mutations in the copper zinc superoxide dismutase could also benefit from this approach. While basic science will provide us with more genes to test, we need to continue our quest to further improve our viral vectors so that they can accommodate larger genes, diffuse over longer distances and infect a specific subpopulation of nerve cells. The rationale to use gene therapy for treating the cause of neurodegenerative is sound. We just need more sweat and hard work.
Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., and Kaspar, B. K. (2009). Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59-65. Gorbatyuk, O. S., Nash, K., Li, S., Gorbatyuk, M., Lewin, A. S., Sullivan, L. F., Mandel, R. J., Chen, W., Meyers, C., and Muzyczka, N. (2009). Alpha-synuclein silencing via AAV mediated RNAi delivery causes nigrostriatal degeneration. Annual Meeting of the Society for Neuroscience, abstract 698.3. Jarraya, B., Boulet, S., Ralph, G. S., Jan, C., Bonvento, G., Azzouz, M., Miskin, J. E., Shin, M., Delzescaux, T., Drouot, X., et al. (2009). Dopamine gene therapy for Parkinsons disease in a nonhuman primate without associated dyskinesia. Sci. Transl. Med. 1, 2ra4. Marks, W. J., Jr., Ostrem, J. L., Verhagen, L., Starr, P. A., Larson, P. S., Bakay, R. A., Taylor, R., Cahn-Weiner, D. A., Stoessl, A. J., Olanow, C. W., et al. (2008). Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinsons disease: an open-label, phase I trial. Lancet Neurol. 7, 400-408.
figure 1. (A) ICV injection of AAV6-GFP results in widespread GFP expression across the brain and spinal cord. High magnification indicating transduction of (B) Purkinje cells of the cerebellum and (C) motor neurons of the spinal cord ventral horn. Scale bar = 100 m.
RESEARCH HIGHLIGHTS
NEURODEGENERATION
ANESThETICS MIMICKING AlZhEIMERS DISEASE

by Vincenzo Fodale and Pravat K. Mandal
Alzheimers disease (AD) is a major neurodegenerative disorder affecting millions of people worldwide. The -amyloid peptide (A), hallmark of the disease, is subject to toxic A aggregation (oligomerization), leading to neurodegeneration. Certain anesthetics, commonly used in clinical practice, promote A aggregation mimicking the molecular mechanism of AD, potentially contributing to accelerate disease onset. The molecular size of anesthetics has a profound influence in promoting the oligomerization process. Smaller sized anesthetics (i.e., inhaled agents, such as halothane, isoflurane and desflurane) are easily accessible to interact with A key residues (G29, A30 and I31), and perturb those residues promoting A oligomerization. Larger sized anesthetics (i.e., intravenous agents, such as propofol and thiopental), due to their size, cannot be accommodated in the loop region containing critical residues, and no A oligomerization is observed. AD is a growing global public health concern; however, for decades, certain anesthetics, suspected of accelerating the AD onset, have been the agents of choice for general anesthesia in the elderly, and in subjects with neurodegenerative diseases and brain damage, all with pathologically high A levels. Pharmaceutical and biotechnology companies are encouraged to synthesize, and hence produce new anesthetic agents with large sized molecules to avoid A oligomerization and increase patient safety.
Comment on: Mandal, P. K., and Fodale, V. (2009). Smaller molecular-sized anaesthetics oligomerize Abeta peptide simulating Alzheimers disease: a relevant issue. Eur. J. Anaesthesiol. 26, 805-806. vfodale@unime.it pravat@nbrc.ac.in
MiRNAs, CAUSE OR CURE

by Judith A. Potashkin
The role that disrupted microRNAs (miRNAs) gene regulation plays in disease development has recently become evident, but little is currently known about their function in neurodegeneration. One giant step in this direction is the recent paper by Junn and colleagues (2009) that shows direct repression of a key component of Lewy bodies found in Parkinsons disease, -synuclein (-Syn), by miR-7. The downregulation of -Syn expression by miR-7 was protective in models of oxidative stress. These findings suggest that miR-7 may be a therapeutic target for Parkinsons disease. Comment on: Junn, E., Lee, K.-W., Jeong, B. S., Chan, T. W., Im, J.-Y., and Mouradian, M. M. (2009). Repression of -synuclein expression and toxicity by microRNA-7. Proc. Natl. Acad. Sci. USA 106, 13052-13057. judy.potashkin@rosalindfranklin.edu
ANXIOUS OR ANXIOlyTIC IN AlZhEIMERS DISEASE?

by Tamotsu hashimoto-Gotoh
It has been reported recently that mice expressing mutant presenilin 2 gene, respon-
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sible for the rare type of familial Alzheimers disease (AD), display anxiolytic-like behaviors (Yuk et al., 2009). This is rather contradictive to the general observation that anxiety/depression often accompanies AD in the early course of pathogenesis. In fact, in human carriers of presenilin 1 mutations, depression can occur early in the course of AD genesis with no information of their genetic status. These observations may, however, not be contradictive, if AD mutations in presenilins 1 and 2 represent loss- and gain-of-function mutations, respectively, in terms of their enzymatic activity as -secretase (Hashimoto-Gotoh et al., 2006). Comment on: Yuk D. Y., Lee Y. K., Nam S. Y., Yun Y. W., Hwang D. Y., Choi D. Y., Oh K. W., and Hong J. T. (2009). Reduced anxiety in the mice expressing mutant (N141I) presenilin 2. J. Neurosci. Res. 87, 522-531. Hashimoto-Gotoh T., Tsujimura, A., and Watanabe, Y. (2006). Presenilins: clarification of contradictory observations using molecular and developmental animal models. J. Kyoto Prefect. Univ. Med. 115, 809-825. Available at: www.eonet.ne.jp/~kpum/Presenilin_files/ Hashimoto_GotohModel.pdf thg@koto.kpu-m.ac.jp
over ones lifetime. These multiple hits are likely pesticides, heavy metals (e.g., iron) and may even be infectious pathogens. Our own recently published work revealed that exposure to a bacterial agent (mimicking an infection) greatly enhanced the neurodegenerative effects (loss of midbrain dopamine neurons) of a subsequently administered pesticide (paraquat; which has been epidemiologically linked to PD). These data reveal that manipulation of the neuroinflammatory immune response (involving microglia) can shape the neuronal impact of environmental insults. Comment on: Mangano, E. N., and Hayley, S. (2009). Inflammatory priming of the substantia nigra influences the impact of later paraquat exposure: Neuroimmune sensitization of neurodegeneration. Neurobiol. Aging 30, 1361-1378. emangano@connect.carleton.ca shawn_hayley@carleton.ca
data suggest a possible mechanism for cellto-cell transmission of -Syn and may provide a critical insight into the mechanism of pathological progression in PD. Comment on: Desplats, P., Lee, H. J., Bae, E. J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., and Lee, S. J. (2009). Proc. Natl. Acad. Sci. USA 106, 13010-13015. anthony.vernon@kcl.ac.uk
DIVERSE SUbSTRATES OF bACE1

by Reema Roshan
IS -SyNUClEIN A PRION?
by Anthony Vernon
PESTICIDES lINKED TO PARKINSONS DISEASE

by Emily N. Mangano and Shawn hayley
Accumulating evidence suggests that vulnerable individuals can develop Parkinsons disease (PD) following exposure to certain combinations of environmental toxins
In many cases of Parkinsons disease (PD), accumulation of aggregated -synuclein (-Syn) undergoes an ascending and predictable pattern of progression through the brain, even spreading to neurons transplanted into the brains of PD patients. Speculatively, this phenomenon may involve a pathological propagation mechanism, as observed in prion diseases. Desplats et al. (2009) provide evidence that -Syn is transmitted by endocytosis to both neighboring neurons and neuronal precursor cells, resulting in formation of LB-like inclusions both in vitro and in vivo. These
Kim et al. (2007) have identified a novel substrate for BACE1 -subunit of voltage gated sodium channel. Certain reports describe NRG-1, IL-1 RII and PSGL-1 as substrate for BACE1 apart from widely studied APP. BACE1 (-site of APP cleaving enzyme) is an aspartic acid protease, predominately present in neurons in the brain. Both level and activity of BACE1 is increased in Alzheimers patients. Consequently, BACE1 inhibitors are of great therapeutic value as they can prevent formation of -amyloid plaques and slow down the pathogenesis of the disease. Diverse substrates of BACE1 hint at a much more general role of BACE1 in other neurological diseases broadening its impact as a drug target. Comment on: Kim, D. Y., Carey, B. W., Wang, H., Ingano, L. A. M., Binshtok, A. M., Wertz, M. H., Pettingell, W. H., He, P., Lee, V. M.-Y., Woolf, C. J., and Kovacs, D. M. (2007). BACE1 regulates voltage-gated sodium channels and neuronal activity. Nature Cell Biol. 9, 755-764. reema.roshan@igib.res.in
CPG DNA ThERAPy FOR AlZhEIMERS DISEASE

Unmethylated CpG DNA, which enhances microglial clearance of soluble oligomeric -amyloid (oA)1-42, may be an effective agent for treating Alzheimers. Doi et al. discovered that microglia, activated with a low dose of CpG (in particular class B and C), do reduce the neurotoxic effect of oA1-42 without producing the usually expected neurotoxic molecules nitric oxide and glutamate. Animal studies also showed that CpG DNA, injected directly into the brain, reduces both cognitive impairment and learning defects in a mouse model of Alzheimers disease. Doi, Y., Mizuno, T., Maki, Y., Jin, S., Mizoguchi, H., Ikeyama, M., Doi, M., Michikawa, M., Takeuchi, H., and Suzumura, A. (2009). Microglia Activated with the Toll-Like Receptor 9 Ligand CpG Attenuate Oligomeric -Amyloid Neurotoxicity in in Vitro and in Vivo Models of Alzheimers Disease. Am. J. Pathol. 175, 2121-2132.
receptor agonists, may affect the mesolimbic reward pathway in the same way as cocaine and methamphetamine, leading to hypersexuality, gambling, and punding; the intense fascination with examining and repeatedly handling an object (Bostwick et al., 2009; Graham et al., 2009). Other obsessions include over-eating, shopping and over-spending, and less destructive behaviors such as compulsive gardening, fishing or hobby work. However, unlike in cocaine or methamphetamine addiction, discontinuation of the medication results in automatic behavioral remission. Bostwick, J. M., Hecksel, K. A., Stevens, S. R. Bower, J. H., and Ahlskog, J. E. (2009). Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease. Mayo Clin. Proc. 84, 310-316. Graham, N. A., Hammond, C. J., and Gold, M. S. (2009). Drug-induced compulsive behaviors: exceptions to the rule. Mayo Clin. Proc. 84, 846-847.
cal but also psychological improvements. The duration of the effect is individual, but most patients do not need any drug treatment for around one year. http://www.xcell-center.com/about/xcellcenter.aspx
NEURODEGENERATIVE DISEASES COUlD bE DETECTED IN ThE EyE

Neurodegenerative processes, which cause Alzheimers, Parkinsons and Huntingtons disease, do not only occur in the brain, e.g., -amyloid deposition also affects retinal nerve cells causing glaucoma. Researchers used a mouse model to study a fluorescent marker that can be used to monitor retinal cell death over hours, days, weeks and even month, at the single-cell level. In a few years time, clinicians may be able to use the dye to visualize and track changes in dementia patients, which facilitates the diagnosis and treatment of neurodegenerative diseases. Cordeiro, M. F., Guo, L., Coxon, K. M., Duggan, J., Nizari, S., Normando, E. M., Sensi, S. L., Sillito, A. M., Fitzke, F. W., Salt, T. E., and Moss, S. E. (2010). Imaging multiple phases of neurodegeneration: a novel approach to assessing cell death in vivo. Cell Death and Disease 1, e3, doi: 10.1038/ cddis.2009.3
NIh AWARDS US$3.7 MIllION FOR hUNTINGTONS DISEASE RESEARCh

The National Institutes of Health (NIH) have awarded US$3.7 million to the consortium formed with the Gladstone Institute of Neurological Disease (GIND) and the Taube-Koret Center for Huntingtons Disease Research. New drug treatments that showed potential in animal studies were found to be ineffective in humans due to molecular differences. Five leading Huntingtons research labs will now use pluripotent stem (iPS) cell technology, which can generate stem cells by reprogramming human adult skin cells, to develop human neurons. These can then be used to develop treatments for Huntingtons disease that can act before the first symptoms appear. htt p://www.new s-medical.ne t/new s/ 20091014/NIH-awards-Gladstone-Instituteconsortium-2437M-for-Huntingtonsdisease-research.aspx
REPEATED CONCUSSIONS lEAD TO EARly DEMENTIA

Retired professional American Football players who had three or more concussions during their career have a higher prevalence of mild cognitive impairment. Blows to the head can also lead to an earlier onset of Alzheimers disease (Guskiewicz et al., 2005). A recent study ordered by the National Football League (NFL) compared players with men from the general US public and found an astonishing 19-fold higher rate of memory problems and forms of dementia among football players aged 30 to 49. Guskiewicz, K. M., Marshall, S. W., Bailes, J., McCrea, M., Cantu, R. C., Randolph, C., and Jordan, B. D. (2005). Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57, 719-726.
PROTECTIVE ROlE OF PRION PROTEIN IDENTIFIED

Accumulation of PrPSc, a misfolded, aggregated form of cellular prion protein (PrPC), causes neurodegeneration. However, the PrPC protein is well conserved between species, raising the question of its function. Bremer and colleagues recently solved the riddle; prion protein expressed by neurons but not by Schwann cells is essential for myelin sheath maintenance of peripheral nerves. Bremer, J., Baumann, F., Tiberi, C., Wessig, C., Fischer, H., Schwarz, P., Steele, A. D., Toyka, K. V., Nave, K.-A., Weis, J., and Aguzzi, A. (2010). Axonal prion protein is required for peripheral myelin maintenance. Nature Neurosci., doi:10.1038/nn.2483 By Nicole Detzer
DOPAMINE AGONIST INDUCED COMPUlSIVE bEhAVIOR IN PARKINSONS PATIENTS

Taking a daily therapeutic dose of pramipexole or ropinirole, both selective D3
STEM CEll TREATMENT FOR PARKINSONS AND MS

The Xcell-Centers in Germany are treating Parkinsons, MS and other diseases with body-own stem cells. Only days later, patients begin to experience not only physi-
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Astrocytes in dnSNARE mouse : Expression of dnSNARE and EGFP (green) co-labelled with GFAP (red) in astrocytes. Courtesy of Jinghui Dong, Tufts University School of Medicine, Boston
FEATURED SCIENTIST
NEURODEGENERATION
SERGE PRZEDbORSKI
octor Serge Przedborski is a famous specialist in neurodegenerative diseases, more specifically in cell death and the processes that lead to it. By treating patients, he realized that medical doctors could diagnose that specific cells were dying, but they could not do more, which led him to study neurodegeneration. Dr. Przedborski became a pioneer in investigating the molecular mechanisms of neuronal death in different models of Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). Dr. Przedborski earned his M.D. at the Universite Libre de Bruxelles (ULB), Belgium, in 1983, followed by an internship and residency in neurology and psychiatry at the ULB-Erasme Medical Center. He obtained his Ph.D. in Neurological Sciences at the ULB School of Medicine. Later on, he moved to Columbia University, New York, where he worked as post-doctoral researcher. In 1991, he became assistant professor of neurology. He is now the Page and William Black Professor of Neurology and professor of pathology at Columbia Universitys College of Physicians and Surgeons in New York. He is also a faculty member of the Center for Neurobiology and Behavior, the scientific director of the Eleanor and Lou Gehrig MDA/ALS Center and a co-director of the Motor Neuron Center at Columbia University. His labs research focuses on explaining the molecular basis of neurodegeneration. His team works on the development of therapeutic strategies to prevent the processes that cause neuronal death, which is the source of many degenerative disorders. His team contributed significantly to the understanding of the molecular mechanism of MPTP (a neurotoxin that causes permanent symptoms of PD) and consequently, the pathogenesis of PD. One of Dr. Przedborskis most interesting results was the demonstration of
the importance of the cascade of deleterious events apoptosis, inflammation and oxidative stress in the death of nigral dopaminergic neurons in PD and of spinal cord motor neurons in ALS. However, he does not expect that the research on apoptosis, even if promising, will solve the enigma of neurodegenerative diseases. Moreover, apoptosis is the last resort of a cell that is already sick. It is more likely that the answer to these diseases would be multiple interventions instead of a single drug, and the anti-apoptotic strategy would be a way to slow the disease, not to stop it. In 2002, he received the Sheila Essey Award from The American Academy of Neurology for his studies on ALS. According to Dr. Przedborski, the death of neurons seems to be activated by suicide programs resulting from neurodegenerative diseases. His work gave hope of finding a way to stop the degeneration of neurons in ALS one day. In 2003, his team found a cheap and easy way to treat Parkinsons disease. They showed that infusion of D--hydroxybutyrate (D--HB) into mice suffering from PD restores impaired brain function and protects against motor skill abnormalities and neurodegeneration. D--HB is already successfully used in epilepsy treatment and may represent a simple way of neuroprotection therapy in the treatment of this disease. In 2007, his team found that astrocyte cells (the most abundant non-neuronal cells in the central nervous system) were not spectators, as previously thought, but key players in neurons death. Astrocytes, which were expressing a mutated form of a gene, superoxide dismutase (SOD1), were killing only the neurons that degenerate in ALS. Consequently, it was deducted that motor neuron death was specifically caused by the astrocytes releasing a toxic factor that was damaging neurons. A solution is to block this toxic factor as early as possible to protect the neurons. This could also help in detecting the illness
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before the clinical signs are visible. Indeed, most patients are treated only when they have symptoms, meaning that the disease already progressed and most of the motor neurons are already dead. Therefore, Dr. Przedborski wanted to learn more about this. He thinks that, eventually, we should be able to check the level of this toxin in the people and be able to treat someone by neutralizing the process leading to degeneration of motor neurons before it is too late. One suggestion was to replace the damaged motor neurons by transplantation of motor neurons created from stem cells. They also found that using embryonic stem cells could be a new tool to study disease mechanisms and to identify drugs to slow ALS, by using them as an in vitro model of ALS.
In summary, this had great implications for stem cell research, earlier ALS diagnosis and possibilities of more targeted interventions. Dr. Przedborskis most recent finding was the identification of a protein that seems to be not only central to the process that causes PD, but that could also play a role in reducing the effect of addictive drugs. The action of this protein (named organic cation transporter 3 or oct3) could resolve one of the remaining issues in understanding the brain damage that cause symptoms, like postural instability, slowness of movement, stiffness or tremor (typical Parkinsonian symptoms). What Dr. Przedborski showed was that this protein, by transporting molecules in or out of the cell, also brings toxins to dying brain cells.
Scientists then identified oct3 as an escort for this toxic molecule out of the astrocytes and into the space around dopamine neurons. This is where another molecule, the dopamine transporter, picks it up and brings it into the neuron itself. When the team blocked oct3 in mice, the dopamine neurons did not die and the toxic molecule remained inside the astrocytes; when oct3 was present in the usual amount, dopamine neurons died as expected. About the role that oct3 plays in the brains response to drugs, it seems that oct3 is critical for helping astrocytes absorb excess dopamine around neurons. When dopamine is not removed quickly, people can feel euphoric, but brain damage can also occur. The finding that oct3 may play a role matches other scientists observations that people in whom oct3 activity is reduced have a higher potential for addiction. Therefore, this protein would also be important in treating depression, as oct3 also removes serotonine from the brain. The goal now is to find a drug able to regulate the concentration of oct3. The protein concentration should decrease in the case of Parkinsons disease, but in the case of addiction it should increase to diminish the effect of a drug. Dr. Przedborski, who is both a researcher and a clinician, finds his patients very inspiring. They all intensely search for any kind of information about their disease and can be very much up-to-date. Because of their knowledge on the latest research findings, expectations of the patients can be a motor, not only for public awareness but also for raising funds. Dr. Przedborski published more than 130 original articles and serves on editorial boards, such as the Journal of Neuroscience, the Journal of Neurochemistry, and Movement Disorders. He is a member of several societies including the American Academy of Neurology, the Huntingtons Disease Society of America, and the Muscular Disease Association. By Nathalie Tzaud
SOCIETY
NEURODEGENERATION
ThE bURGEONING AlZhEIMERS DISEASE CRISIS

by William Thies
he 2009 World Alzheimer Report, released on World Alzheimers Day by Alzheimers Disease International and its member organizations, including the Alzheimers Association, shows that the number of people with Alzheimers and other dementias is rising substantially worldwide. The impact on families, governments, and national healthcare systems will be immense, and it is urgent that governments respond to this significant global public health threat. According to the report, more than 35 million people worldwide will have Alzheimers disease or another dementia in 2010. This is a 10% increase over previous global dementia prevalence reported in the Lancet in 2005. Even more alarming, Alzheimers and dementia prevalence will nearly double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. In 2007, the worldwide economic cost of dementia was estimated as US$315 billion annually, and that cost is certainly higher now since the prevalence numbers are higher. However, Alzheimers and dementia have physical, psychological and economic impact not only on the person with the disease, but also on caregivers, the persons family and friends, healthcare systems, and society. In the United States alone, according to the Alzheimers Association 2009 Alzheimers Disease Facts and Figures:
There are as many as 5.3 million Americans living with Alzheimers disease and that number is expected to grow to as many as 16 million by 2050. By 2010, there will be nearly half a million new cases of Alzheimers each year in the US, and by 2050, there will be nearly a million new cases per year. Every 70 seconds, someone in America develops Alzheimers disease and by mid-century someone will develop Alzheimers every 33 seconds. Medicare currently spends more than three times as much on people with Alzheimers than on the average beneficiary. The Alzheimers Study Group, an independent panel co-chaired by former House Speaker Newt Gingrich and former Senator Bob Kerrey, recently found that those with Alzheimers will cost taxpayers US$20 trillion in Medicare and Medicaid costs over the next 40 years equal to 25 stimulus bills over the next four decades. With more people worldwide living longer lives, there is an increased risk for developing Alzheimers and other dementias, and a fundamental shift in the urgency in addressing this threat is absolutely necessary. While several leading industrialized nations including France, the United Kingdom, and Australia have developed comprehensive national dementia plans to address Alzheimers, the United States does not have a National Alzheimer Strategic Plan. This has to change now.
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The Alzheimers Association strongly believes the US must take a leadership role in confronting this epidemic, and develop a plan to address it, which is why the Alzheimers Association is urging members of Congress to support and pass the Alzheimers Breakthrough Act. This legislation would provide a significant funding increase for Alzheimers research at the National Institutes of Health to US$2 billion advancing the pursuit of better diagnostics and treatments that could save millions of lives and billions of dollars for Medicare and Medicaid. The Alzheimers Association enthusiastically supports this legislation and sees it as a necessary vehicle to change the paradigm as we know it today.
William thies, Ph.D., is Chief Medical and Scientific Officer for the Alzheimers Association. He oversees the worlds largest private, non-profit Alzheimers research grants program. He led the integration into the Alzheimers Association of the International Conference on Alzheimers Disease and Related Disorders (ICAD), the worlds leading forum on dementia research. Thies played a key role in launching Alzheimers & Dementia: The Journal of the Alzheimers Association, and in establishing the Associations Research Roundtable, a consortium of senior scientists from industry, academia and government. william.thies@alz.org
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A PATIENT WITh AlZhEIMERS DISEASE

by Martin J. Sadowski
Are dementia and neurodegenerative diseases a normal part of aging? They certainly are not. Graceful aging may be associated with some mild decline in cognitive performance, including decreased attention span (why did I walk into this room?), problems with multitasking or difficulties with instant retrieval of the wealth of information acquired throughout the life span; but, a dementia is the cognitive disability preventing proper functioning and conducting activities of basic living, and is always a manifestation of pathological processes affecting the brain. Since the symptoms of AD evolve slowly, patients and their families may not be aware about the disease onset. The first most important thing after being diagnosed with AD is to acknowledge the fact of having the disease and to accept help from other family members in terms of supervising financial matters, investing, legal matters, and medical care, including taking daily medications. When talking to
Martin J. sadowski, M.D., Ph.D., is an Assistant Professor of Neurology, Psychiatry, and Pharmacology at the New York University School of Medicine. His private practice, academic teaching, writing, and research are focused on early diagnosis of AD and therapeutic interventions preventing AD. sadowm01@med.nyu.edu
patients with newly diagnosed early AD, I use the example of a broken hand placed in a cast. I usually use this analogy to explain to the patient that having a broken hand does not change the person you are, it causes only some limitations in daily life and makes you more dependent on others who are eager to help you with some daily activities. The same is when your memory does not serve you well; it does not preclude you from enjoying life and family interaction. It requires from you acceptance of some help from your relatives. This conversation is frequently critical to reduce possible family tensions and stress. A person in the early stage of AD is the same person she/he was before the onset of the disease. AD does not disturb personality or sense of humor until a very late stage. Therefore, it is strongly encouraged for patients to continue their social life. One should be, however, aware of memory problems associated with AD and develop ways to overcome them, what many properly guided patients do. Examples include: keeping notes on appointments and things to do, having pictures of new family members with their names (e.g., newly born grandchildren), and accept the fact that memory of other peers may serve them better. Therefore, one should get into a habit of not arguing about facts for which recollection may not be as perfect as it used to be.
BOOkS
ThE ChANGING bRAIN AlZhEIMERS DISEASE AND ADVANCES IN NEUROSCIENCE
by ira b. black Oxford University Press (2002) In his book, Ira Black tells the fascinating story of modern neuroscience. In the mid 1990s, a revolutionary new conception of the brain emerged instead of the traditional view that the brains role in perception, memory, learning, and emotions was based on a static, non-renewable network of brain cells and connections, research revealed that the human brain is an ever-changing, fantastically complex system that is continually being shaped and reshaped by a subtle interplay of genetic clues and life experiences. To bridge the gap between abstract concepts and real-world experience, Dr. Black draws upon his expertise as a clinical neurologist to provide a dramatic account the fictionalized story of a successful investment banker named Enoch Wallace and his battle with Alzheimers disease that vividly illuminates the narrative. From his first fleeting memory lapses to his final descent into dementia, each step in Wallaces decline becomes a window into another aspect of brain function and the latest groundbreaking research in neuroscience.
lEGAl AND EThICAl ASPECTS OF DEMENTIA

by Daniel Marson
Alzheimers disease (AD) and related neurodegenerative disorders implicate core legal and ethical issues that transcend national and cultural setting. First, AD involves progressive cognitive impairment and ultimately loss of an individuals decision making capacities (Melnick and Dubler, 1984; Marson and Solomon, in press). Over time, a person with AD gradually loses the capacity to manage money, use transportation, make personal medical decisions and, ultimately, to manage all personal affairs. This gradual loss of autonomous decision making in all spheres of life eventually triggers some form of patient and family engagement with the local legal system. Although legal provisions and procedures will vary across countries and jurisdictions, the key legal goals remain the same: to protect the health and welfare of the individual with dementia; and also to protect and preserve his/her property and estate by formally instituting transfer of decisional authority to another person or institution. Such transfers of decisional authority may be accomplished prior to the individuals loss of competency, in the form of advance directives, such as durable powers of attorney, living trusts or living wills. These legal devices permit more informal and relatively inexpensive transfer of authority, but require the individual to still be
Daniel Marson, J.D., Ph.D., is a tenured Professor in the Department of Neurology at the University of Alabama at Birmingham where he serves as Director of the Alzheimers Disease Center and also Director of the Division of Neuropsychology. Dr. Marson graduated from Carleton College in 1976, earned a J.D. degree in 1981 at the University of Chicago Law School, and completed his Ph.D. in Clinical Psychology in 1990 at Northwestern University Medical School. Research interests include medical decision-making capacity, financial capacity, and testamentary capacity in AD and related dementias. dmarson@uab.edu
legally competent to execute the directive. Other transfers of decisional authority may occur more formally, through the operation of a formal court hearing and the legal determination of a judge or legal professional. Guardianship and conservatorship proceedings are examples of such formal legal transfers of authority, and often occur when an individual has lost legal competency to execute advance directives, or when formal court oversight of the patient is needed due to conflicts among involved family members. Secondly, AD and other neurodegenerative dementing disorders are distinctly human disease processes that impair higher cortical and also subcortical brain functioning (Melnick and Dubler, 1984; Marson and Solomon, in press). As a result, research progress in treating and ultimately curing these diseases depends, in substantial part, on the use of human research participants with dementia, and also human blood, cerebrospinal fluid and tissue samples. While
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such research efforts are imperative, they raise a host of ethical and legal issues that center on obtaining research informed consent from the person with AD. These issues include the need to assess a potential participants research consent capacity; the alternative of obtaining proxy consent for research participation when the participant can no longer give informed consent; the continuing need to receive assent to study involvement by participants who lack capacity to consent; and the role of institutional review boards (IRBs) to oversee and monitor research with cognitively vulnerable individuals. Thirdly, AD and related neurodegenerative dementias are protracted illnesses that primarily affect adults in the later stages of life (Melnick and Dubler, 1984; Marson and Solomon, in press). Persons with AD live approximately 3 to 8 years after diagnosis (Brookmeyer et al., 2002), and the average lifespan following symptom onset in Parkinsons disease can be 20
years or more. As these diseases progress, the affected individual typically experiences increasing cognitive, emotional, motor and functional declines; development of substantial disabilities; emergence of other medical health problems; and a need for ever increasing levels of care, often leading ultimately to a terminal vegetative state. Thus, the latter stages of these diseases are associated with advanced biological and functional decline, and raise associated ethical concerns about quality of life, end of life, and quality of death (Whitehouse, 2000). Clinicians working with advanced dementia patients face over time challenging ethical and legal issues, such as medical resource allocation; medical futility; palliative care and assignment to hospice; and, in some countries and jurisdictions, assisted suicide and euthanasia. In summary, AD and related disorders implicate a range of legal and ethical issues that are inextricably tied to core dimensions of neurodegenerative dementia: loss of deci-
sional capacity in all spheres of life; the need for patients with dementia to participate as human research subjects; and the progressive disability, medical care needs, and end of life issues inherent in these dementing disorders of aging.
RefeRences
Brookmeyer. R., Corrada, M. M., Curriero, F. C., Kawas, C. (2002). Survival following a diagnosis of Alzheimer disease. Arch. Neurol. 59, 1764-1767. Marson, D., and Solomon, A. (in press). Ethical and legal issues in geriatric neuropsychiatry, in Textbook of Geriatric Neuropsychiatry, 3rd edition, ed. Cummings, J., Coffey, E., George, M., and Weintraub (D. Washington, DC: American Psychiatric Press Institute). Melnick. V., and Dubler, N. (1984). Clinical research in senile dementia of the Alzheimer type: Suggested guidelines addressing the ethical and legal issues. J. Am. Geriat. Soc. 32, 531-536. Whitehouse, P. (2000). Ethical issues, in Textbook of Geriatric Neuropsychiatry, 2nd edition, ed. Coffey, C. E., and Cummings, J. L. (Washington, DC: American Psychiatric Press), 935-944.
CAREGIVERS OF ADUlTS WITh COGNITIVE IMPAIRMENTS: FUTURE ChAllENGES

by Kathleen Kelly
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Kathleen Kelly is Executive Director of the Family Caregiver Alliance and the National Center on Caregiving in San Francisco. Ms. Kelly has extensive experience in the fields of aging, long-term care and public policy specific to informal caregivers. Ms. Kelly has focused attention on policies and practices within larger systems to incorporate families as care partners across service settings. She sits on a number of national advisory boards and is a frequent speaker at conferences and the media on long-term care. kkelly@caregiver.org
RefeRences
Brookmeyer, R. Johnson, E., Ziegler-Graham, K., and Arrighi, H. M. (2007). Forecasting the burden of Alzheimers disease. Alzheimers and Dementia 3, 186-191. Family Caregiver Alliance (2005). A 20-year partnership in caring. San Francisco, Family Caregiver Alliance. Langa K. M., Chernew, M., Kabeto, M., Herzog, A. R., Ofstedal, M. B., Willis, R., Wallace, R., Mucha, L., Straus, W., and Fendrick, A. M. (2001). National estimates of the quantity and cost of informal caregiving for the elderly with dementia. J. Gen. Intern. Med. 16, 770-778. Montgomery, A., and Feinberg, L. (2003). Policy Brief: The road to recognition: international review of public policies to support family and informal caregiving. Family Caregiver Alliance. United Nations, Department of Economic and Social Affairs Population (2007). World Population Ageing 2007.
A dramatic demographic shift is taking place worldwide as the populations in developing and developed nations face an aging population. In 2007, 11% of the global population was over 60, and the percentage is expected to rise to nearly 22% by 2050 (United Nations, 2007). In developed countries, nearly a third of the population is expected to be over the age of 60 by 2050 with those over 80 years currently increasing at 3.9% annually. As age increases, the prevalence of chronic conditions and cognitive impairments also increases. This is particularly true of cognitive impairments, such as Alzheimers disease and related conditions. In 2006, the prevalence of Alzheimers disease was 26.6 million persons, with an expected quadrupling of this number by 2050 (Brookmeyer et al., 2007). This demographic shift will affect society at its core, with changes across the social, economic and healthcare sectors. For many developed countries, such as members of the European Union, the United States and Asian countries such as Japan, recognition of these changes and the formulation of public policies to address them have been well underway for decades. In practical ways, developing countries have looked to increase support for older adults and their families through a greater emphasis on community care options that keep older adults in the community and delay more costly options (Montgomery and Feinberg, 2003). Over the past three decades, informal caregivers have been increasingly recognized for their pivotal role in the long-term care system. Indeed, informal caregivers will
likely continue to be the largest source of support and assistance to older adults. In the United States, it is estimated that 37 million informal caregivers will be providing care by 2050, an increase of 85% from 2000. However, this expected demand also has an economic, social and health cost to informal caregivers. Informal caregivers are largely women, with the majority between the age of 35 and 64. For those over 65, it may mean that older spouses are the primary caregiver bringing along their own health conditions into the caregiving situation. However, adult children are assuming caregiving roles in ever greater numbers, exactly at a time when they are also juggling work, family and planning for their own retirement. In the United States, women comprise half of the workforce, and 40% are the primary breadwinners in the family. For half of all families, two incomes are relied upon and 20% of families are headed by single mothers. More women than men are earning college and advanced degrees, and are holding almost 40% of professional and managerial positions. This unprecedented shift of women into the workforce creates an informal caregiving gap that is likely not to be closed soon. For informal caregivers, the time spent providing assistance may range from a few hours per week to significantly more time, as the older adult develops multiple chronic impairments. For caregivers of adults with Alzheimers disease, the hours per week can reach 46.1 or more (Langa et al., 2001). An estimated 43% of individuals
with Alzheimers disease need a level of care equivalent to that of a nursing facility. On average, informal caregivers spend 4.3 years providing care (Family Caregiver Alliance, 2005); although, caregiving for 5 years or longer is not unusual. The impact of caregiving on health has been well documented and typical risks involve increased blood pressure and insulin levels, impaired immune systems, and increased risk of cardiovascular disease. Intertwined are the increased psychological risks of depression, stress, and higher use of prescription and psychotropic medications. Caregivers found most at risk for early mortality are older spousal caregivers caring for those with Alzheimers disease. Public policies that encompass the informal caregiver can do much to remedy the situation by first recognizing the caregiver and family as full partners in a health care plan. An assessment of the caregivers own needs for practical and emotional support should be a part of every care plan for older adults. Increased funding for community supports, as well as workplace policies that offer flex time, paid time off and nondiscrimination toward caregiver employees could address work and family conflicts. Finally, several countries are providing some financial relief in the form of tax credits, deductions and direct payment to family members who provide assistance. With the shift in the aging population looming, all societal and governmental resources must be incorporated to create caregiver and aging-friendly communities for the future.
hOME CAREGIVERS: ThE hIDDEN PATIENTS

In 2008, 10 million people (grown-up children, spouses, friends and neighbors) in the US provided 8.5 billion hours of unpaid care; this contribution has a value of US$94.4 billion (Alzheimers Association, 2009). It is also worth pointing out that 25% of informal caregivers look after someone full-time. Many take care of a parent or grandparent, because they feel, having been raised by them and supported all their life, it is now their turn to give something back. Others take care of their spouse, with whom they spent decades, raised children, and enjoyed their lives together with. At the early stages of dementia, the parent or partner might not remember things and sometimes act like a child: not wanting to eat or bathe or disliking the way you dress them; but, as the disease progresses, the person may even become hostile or aggressive, or engage in sexually inappropriate behaviors. How hard must it be to watch dementia take away every ounce of dignity from a loved one? Eventually, the caregiver looks after a person who has gradually become a stranger to them and who does not even recognize them anymore. All this causes stress, depression and anxiety. The term caregiver burden is used to describe the combination of physical, emotional, social and financial problems resulting from informal caretaking (e.g., Chou et al., 2003). How long does it take and what are the factors that promote caretakers syndrome and, eventually, caretaker burnout? Surprisingly, there is no link between the level of disease progression or years spent caring, but people who look after a person with whom they have a strong bond of love or friendship can be severely affected (Karlikaya et al., 2005). Feelings like: you have to do it all alone and you should do it better, or is the person safe, leads to withdrawal from family and friends, and hobbies usually enjoyed. Financial worries and fear of losing their job add to it further, since caring for a relative or spouse usually forces the carer to work part-time. In a lot of cases, the poor self-rated health status and life satisfaction is projected onto the person they look after, and home caretakers sometimes do not realized that their spouse or parent enjoys the good moments and lives with the fact that at some point they will be lost in dementia. Of course it is hard, if it is just you and no one else. Therefore, it is vital for informal caretakers not to forget about their own needs and set aside time every day to pursue their own interests, even if it is just for an hour or two. This has been recognized by family practitioners (Parks and Novielli, 2000)
and caregiver burden questionnaires are available that help assess the situation (Chou et al., 2003). Sadly, informal caregiving can also harm the person more severely because there is an increased risk of having high levels of stress hormones, reduced immune function, slow wound healing, and new hypertension and coronary heart disease (Alzheimers Association, 2009). Spouses, because of their own advanced age, are affected the most, and require treatment in a hospital themselves and, as reported in a study by Christakis and Allison (2006), 9% of husbands and 5% of wives die within the first year after their partner has been
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hospitalized for dementia. These findings make it blindingly obvious that not only the dementia patients need support from the health care and social care systems; their informal caretakers need to be integrated likewise. Acknowledgments I would like to thank all the informal caregivers who openly talk in online forums about the ups and downs of looking after their parent or grandparent suffering from Alzheimers disease or other form of dementia; they truly inspired this article. By Nicole Detzer
RefeRences
Alzheimers Association (2009). Alzheimers Disease Facts and Figures. http://www.alz.org/national/documents/report_alzfactsfigures2009.pdf Chou, K. R., Chu, H., Tseng, C. L., and Lu, R. B. (2003). The measurement of caregiver burden. J. Med. Sci. 23, 73-82. Christakis, N. A, and Allison, P. D. (2006). Mortality after the hospitalization of a spouse. New Engl. J. Med. 354, 719-730. Karlikaya, G., Yukse, G., Varlibas, F. and Tireli, H. (2005).Caregiver burden in dementia: a study in the Turkish population. The Internet Journal of Neurology 4, ISSN: 1531-295X. Parks, S. M., and Novielli, K. D. (2000). A practical guide to caring for caregivers. Am. Fam. Physician 62, 2613-2620.
ThE COST OF AlZhEIMERS DISEASE

The US-American Alzheimers Association is a non-profit organization dedicated to promote support and research on Alzheimers disease. To raise awareness and show that Alzheimers affects everybody, at least financially, the cost for businesses and the health care system are related to the dividends that investment into Alzheimers research implies.
Medicare spending on beneficiaries with Alzheimers (in billion Us$)

1.200 Baseline estimates Delayed onset and slowed progression 1.000
800
600
400
200
0 2000 2010 2015 2020 2025 2030 2035 2040 2045 2050
Alzheimers medication delays the outbreak of the disease and slows progression of the medical conditions of Alzheimers and other dementias. Assuming that research leads to more powerful medications, investment into this research would generate savings of up to US$88 billion in 2020 and around US$440 billion in 20501.
www.alz.org/national/documents/report_savinglivessavingmoney.pdf
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Average per person annual payments by source (in Us$)

16.000 14.000 12.000 10.000 8.000 6.000 4.000 2.000 0 Beneficiaries with no Alzheimers or other Dementia Beneficiaries with Alzheimers or other Dementia
Med icar e
Med icaid
P insu rivate ranc e
Outof-p ocke t
The average payment per beneficiary, aged 65 years or older, with Alzheimers disease or other dementias summed up to US$33 billion. In comparison, disbursement for other policy holders in the same age group amounts US$ 10.6 billion (2004)2.
the cost of Alzheimers for Us businesses (in billion Us$)

Business contributions to health care (24.4) Additional employee assistance programs (0.1) Business taxes for federal research programs (0.2) Temporary worker replacement fees (0.7) Continuing insurance for workers on leave (1.2) Replacement costs of caregivers (6.2)
Unc omp ensa ted care
O sour ther ces
HMO
Absenteeism of caregivers (10.2)
Productivity losses due to caregivers absenteeism (18.0)
The total cost of Alzheimers for US companies equaled $61 billion in 2002. Of this amount, 55% are related to the cost of Alzheimers caregivers and around 40% are related to the companies contribution to healthcare3. By Julia Alexander
2 3
www.alz.org/national/documents/report_alzfactsfigures2009.pdf www.alz.org/national/documents/report_alzcosttobusiness.pdf
BOOkS
NEURODEGENERATIVE DISEASES: NEURObIOlOGy, PAThOGENESIS AND ThERAPEUTICS
edited by M. flint beal, Anthony e. lang and Albert ludolph Cambridge University Press (2005) Neurodegenerative diseases are major contributors to disability and disease; Alzheimers and Parkinsons disease being the most prevalent. This major reference reviews the rapidly advancing knowledge of pathogenesis and treatment of neurodegenerative diseases in the context of a comprehensive survey of each disease and its clinical features. The editors and contributors are among the leading international experts in the field. Covering basic science, diagnostic tools and therapeutic approaches, the book focuses on all aspects of neurodegenerative disease, including the normal aging process. The dementias, prion diseases, Parkinsons disease and atypical Parkinsonisms, neurodegenerative ataxias, motor neuron diseases, degenerative diseases with chorea, iron and copper disorders, and mitochondrial diseases, are all methodically presented and discussed, and extensively illustrated. In each case, the underlying genetics, neuropathological and clinical issues are fully reviewed, making this the most complete as well as the most authoritative reference available to clinicians and neuroscientists.
DEMENTIA UNDERESTIMATED
Sir Terry Pratchett, world-famous British author of the Discworld novels, publically announced in December 2007 that he was suffering from early-onset Alzheimers disease , at the age of only 59. As a result, Pratchett made a substantial donation to the Alzheimers Research Trust, the UKs leading dementia research charity, and became a patron of the trust. As part of his speech during the event Dementia Decade: a cure by 2020? held in September 2009, Terry Pratchett said1: We are facing, to use the term said to me by one of the leading US researchers, a worldwide tsunami of Alzheimers and other dementia diseases (). Is there going to be a government of any stripe in England willing to put its money where its mouth is and fund changes? Or will dementia remain the most feared disease of the over 55s? Theres only two ways it can go; researchers, with as much help as you can give them, may come up with something that reduces the effects of this dreadful, inhuman disease, or we will have to face the consequences of our failure to prevent the final years of many of us being a long bad dream. The strain on carers and their support is bad enough now; before very long the effects on the health service and society itself, will be unbearable. What is unthinkable is to do nothing at all. This is not the first time Sir Pratchett has critically pointed out the problems the government has to solve. Greg Mulholland, Liberal Democrat MP and Health Spokesperson, who arranged a meeting between Sir Pratchett and the Prime Minister in November 2008, elucidated1: Dementia costs the UK economy more than heart disease, cancer and strokes combined (Figure 1)2, yet less than 3% of the governments research budget is spent on [dementia] research. This is shameful. More must be done. If we dont increase research funding then well be no closer to understanding dementia or addressing the devastating impact that it has on thousands of people.
1
figure 1. the comparative societal costs of cancer, ischaemic heart disease, stroke and dementia in the UK2
18
16
14
12 costs ( billions)
10
0 Cancer Heart disease Stroke Dementia
Sir Terry Pratchett addresses Lib Dem conference as voters back dementia research campaign published September 22, 2009, at www.alzheimers.org.uk/ site/scripts/news_article.php?newsID=538 World Alzheimer Report 2009, Alzheimers Disease International
informal costs: unpaid care costs by family members or others including their lost opportunity to earn income formal costs: health care, social/community care, respite and long-term residential or nursing home care costs
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So, will dementia remain the most feared disease of the over 55s? Currently, no help seems to be on its way. According the US Alzheimers Association Facts and Figures 2009, the number of deaths caused by Alzheimers increased by 47.1% between 2000 and 2006 (Figure 2)3. Still, the condition and its impact on public health has been significantly underreported and underestimated, and judging by the small number of research papers published on dementia in the past ten years (Figure 3)2 16-times more articles have been published on cancer it would be a miracle if anything changes soon. The World Alzheimer Report 2009 includes a correlation study between research effort, contribution to mortality and disability, which concludes: The more disabling the disease, the less it has been researched () [, but] the greater the disease contribution to mortality, the more it has been researched.
figure 3. number of related research articles published in the past ten years (for six major chronic diseases)2
Cancer: 701,487 Dementia: 44,168 Arthritis: 64,080 Stroke: 87,973
Mental disorders: 233,872
Heart disease: 476,487
figure 2. percentage changes in selected causes of death between 2000 and 20063
Alzheimers Disease a,c Stroke a,c Prostrate Cancer b,d Breast Cancer b,d Heart Disease a,c
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a b c d
Considering that research on dementia is heavily underfunded, more actions like easyJets current fund raising for the Alzheimers Society are needed worldwide: Lynda Bellingham, Alzheimers Society Ambassador4 I am delighted that easyJet and their passengers have raised over 420,000. This will help people live well with dementia today and fund research to find a cure for tomorrow. () Alzheimers Society relies upon the generosity of organisations like easyJet, their staff and passengers, to continue to provide information, education, support and care to families when they need it most. Andy Harrison, Chief Executive of easyJet, adds: () There are over five million people with dementia in Europe making it a truly important cause for our staff and passengers. We look forward to continuing to raise funds for Alzheimers Society in 2010 and reaching our target of 1million! By Nicole Detzer
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National Center for Health Statistics. Deaths: Final Data for 2000. American Cancer Society. Cancer Facts and Figures 2000. Heron et al. American Cancer Society. Cancer Facts and Figures 2006.
Alzheimers Association, 2009 Alzheimers Disease Facts and Figures alzheimers.org.uk/site/scripts/news_article.php?newsID=560
DEMENTIA WORLWIDE
NEURODEGENERATION
canada 356.241
UsA 3.057.068
Mexico 358.900 guatemala 25.538
cuba 86.543
venezuela 73.811 colombia 153.424
peru 87.024 bolivia 20.555
brazil 576.689
paraguay 13.121 Argentina 253.069
chile 82.437
THIS MAP PROVIDES A GLOBAL VIEW OF DEMENTIA PREVELENCE IN SELECTED COUNTRIES IN 2005.
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sweden 141.232 United Kingdom 811.673 france 796.228 spain 541.895 Marocco 73.238 Algeria 65.686 libya 11.958 niger 15.020 nigeria 197.671 italy 849.957 russian federation 1.173.598 germany 1.086.789 Ukraine 475.846
Kazakhstan 76.110 Uzbekistan 76.010 Japan 1.809.133
turkey 238.847 iraq israel 52.985 51.342 egypt 161.587
iran 203.339 pakistan 324.552 saudi Arabia 40.830 india 3.150.792
china 5.562.401 bangladesh 243.600 thailand 252.699
sudan 56.240 ethiopia 97.804 Kenya 49.299
vietnam 276.424
philippines 174.063
Dr congo 86.886 Angola 20.732
indonesia 600.145
Madagascar 26.090 Australia 188.599 south Africa 76.225
Adapted from: Wimo, A., Winblad, B., and Jnsson, L. (2007). An estimate of the total worldwide societal cost of dementia in 2005. Alzheimers & Dementia 3, doi: 10.1016/j.jalz.2007.02.001
FOUNDATION
NEURODEGENERATION
CURRENT STATE OF FUNDING FOR NEURODEGENERATION RESEARCh

everal initiatives have been taken around the world to tackle the major human burden of neurodegenerative disease, which is growing at an alarming rate as the elderly population increases worldwide. Most projects are financed by intergovernmental research agencies and research councils, such as the NIH, the European Union, the Wellcome Trust joint initiative with the British Medical Council in the UK, and the Australian NHMRC global funding program for neuroscience disorders.
ing in 2009 into neurodegeneration research by disease area.
European Union funding for neurodegenerative research

The European Union (EU) supports neurodegenerative diseases-related research through the current 6th Framework Programme (FP6) spread over several years and dedicated to collaborative research undertaken by the European consortia ERA-Net NEURON partners2 selected on the basis of peer-review by independent experts. The consortia decided recently to launch their first joint call for proposals in this area called the European research projects on neurodegenerative diseases of the central nervous system. Up to now, 59 collaborative proposals were submitted comprising 234 subprojects (principal investigators), and 12 projects comprising 45 subprojects (principal investigators) from 10 countries were successful. The total
2
National Institutes of health funding for neurodegenerative research

The NIH annually invest over US$28 billion in medical research. Composed of 27 institutes and centers, more than 83% of the NIHs funding is awarded through almost 50,000 competitive grants to more than 325,000 researchers at over 3,000 universities. Total NIH investment in neurodegeneration research is U$1.1 billion of a total US$5 billion of neuroscience funding per year. The National Institute of Neurological Disorders and Stroke (NINDS) allocates 35% to basic (not assigned for disease), 35% to disease related, and 30% to projects assigned as clinical. 70% of extramural dollars are invested in investigator-led research, whereas 20% is spent on clinical trials1. Figure 1 shows the breakdown of NIH fund1
MRC strategic review of neurodegeneration, report of the Strategic Review Group, February 2008, p. 21.
13 funding organizations participated in the first ERANet NEURON joint call for proposals European research projects on neurodegenerative diseases of the central nervous system: Austrian Science Fund (FWF), Austria; Academy of Finland (AKA), Finland; National Research Agency (ANR), France; Chief Scientist Office, Israel Ministry of Health (CSO-MOH), Israel; Federal Ministry of Education and Research (BMBF), Germany; Ministry of Health (MOH), Italy; National Research Fund (FNR), Luxemburg; Ministry of Science and Higher Education (MNiSW), Poland; National Authority for Scientific Research Ministry of Education, Research and Youth (ANCS MECT), Romania; Ministry of Education and Science (MEC), Spain; Institute of Health Carlos III (ISCIII), Spain; Swedish Research Council (SRC), Sweden; Medical Research Council (MRC), UK.
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Other neurodegenerative diseases (49%) Huntingtons disease (3%) Amyotrophic lateral sclerosis (3%) Parkinsons disease (9%)
Multiple sclerosis (11%)
funding volume amounted to about 10 million for 3 years3 from 2009 until 2012.
UK funding of neurodegenerative research

The Wellcome Trust joint initiative with the Medical Research Council, UK the largest two medical research funders in the UK was launched in 2008 to boost research into neurodegenerative diseases through a funding program that allocates 30 million. The program aims to encourage collaborations between research groups and enables scientists to better understand the causes of neurodegenerative diseases, leading to improved early diagnosis and more effective therapies4.
Alzheimers disease and dementia (25%)
figure 1. Breakdown of NIH 2009 funding (in million US$) in neurodegeneration research by disease area.
20
Australian National health & Medical Research Council (NhMRC) funding for neurodegenerative research
According to a representative of the NHMRCs statistic unit interviewed by Frontiers, most NHMRC funding of neurodegenerative diseases is covered by the neuroscience disorders dataset. No dataset specific to neurodegenerative disorders is recorded at this time. Only Alzheimers and other dementias are covered in a separate dataset; Figure 2 shows the funding for the years 2000-2008. By Shamsa Abdulrasak
3 4
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www.gesundheitsforschung-bmbf.de/en/2237.php www.wellcome.ac.uk/Funding/Strategic-awards/ Past-funding/Neurodegenerative-DiseasesInitiative/index.htm
2000
2001
2002
2003
2004
2005
2006
2007
2008
Figure 2. NHMRC Funding 2000-2008 of Alzheimers disease and dementia (in million A$).
FOUNDATION HIGHLIGHTS
NEURODEGENERATION
hEREDITARy DISEASE FOUNDATION

location: New york, Ny, USA www.hdfoundation.org
Dr. Carl Johnson, Executive Director for Science of the Hereditary Disease Foundation, kindly accepted to contribute an interview in which he describes the funding activities into Huntingtons disease research. The Hereditary Disease Foundation (HDF) aims to cure this genetic illness by supporting basic biomedical research. The HDF was started by Dr. Milton Wexler, in 1968, when his wife was diagnosed with Huntingtons disease (HD). The foundation uses a variety of strategies workshops, grants, fellowships, and targeted research contracts to solve the mysteries of this genetic disease and develop new treatments and cures. HDF uses Huntingtons disease as a model for hereditary disease research because it is triggered by a mutation of one single gene. Progress toward treatment or a cure could be instrumental in finding ways to treat other illnesses with more complex genetics including Parkinsons, Alzheimers, Lou Gehrigs disease (ALS), depression, schizophrenia and cancer. The foundation annually allocates US$50,000 per grant and US$50,00060,000 per year for their two-year fellowships. Research contracts vary from US$50,000 to US$250,000 per year. Awardees are located mostly in the US and Europe, though there is no restriction imposed by the HDF on where the research is performed. The foundation supports research projects that will contribute to identifying and understanding the basic defect in Huntingtons disease. Areas of interest include trinucleotide expansions,
animal models, gene therapy, neurobiology and development of the basal ganglia, cell survival and death, and intercellular signaling in striatal neurons. The foundation played a key role in the discovery of the HD gene, which was localized in 1983 and isolated in 1993. The HDF recruited and supported more than 100 scientists worldwide who worked together as the Huntingtons Disease Collaborative Research Group in a ten-year search to capture the gene. The New York Times called the quest for the HD gene legendary in less than a decade; the gene itself, the most coveted treasure in molecular biology. New technologies developed during the HD gene search supported by the Hereditary Disease Foundation have been widely used in mapping genes for other disorders including cystic fibrosis, Parkinsons, Alzheimers, cancer, heart disease and mental illness. These successes helped to launch the Human Genome Project. Recent scientific research grants include: The Basic Research Grants Program supports projects that contribute to identifying and understanding the fundamental defects in Huntingtons disease and related disorders. The John J. Wasmuth Postdoctoral Fellowships are named in honor of the late John Jacob Wasmuth, an essential member of the Huntingtons Disease Collaborative Research Group. Our hope is that the researchers receiving these fellowships bearing his name will seek Johns level of imagination, rigor, creativity and spirit. The Lieberman Award is presented annually to a worthy scientist, thanks to the generosity of Harry Lieberman, a trustee of the Hereditary Disease Foundation. The Milton Wexler Postdoctoral Fellowship Award is named after the founder of the Hereditary Disease Foundation. The
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Hereditary Disease Foundation restricts this annual award to research highly relevant to curing Huntingtons disease. Regarding the evolution of the research, Dr. Johnson explains that, following the discovery of the genetic mutation that causes HD, the focus of the foundation has been on the discovery of mechanisms of pathogenesis in Huntingtons disease, i.e., in what cells and how does the mutant protein generated by the mutant HD gene cause the changes in cellular function that lead to the phenotypes of the disease. This is an extremely difficult problem. Conclusions from these studies are validated most often by genetic manipulations of the putative pathogenic mechanism in accurate mouse models of the disease. Once a mechanism is validated, it is then investigated in detail to identify putative drug targets for reversing or correcting the causative changes and a drug discovery effort is initiated, most often in collaboration with a corporate/ pharma partner. The status of these efforts is that a large number of changes in cellular function in many different cell types have been identified; a subset of these have been validated and drug discovery efforts are underway within a number of companies (e.g., Alnylam Pharmaceuticals) and a collaboration of Novartis with Massachusetts General Hospital and MIT that the HDF helped to encourage and organize. One of the goals of the creation of MIND (MassGeneral Institute for Neurodegenerative Disease) five years ago was to enlist interest from pharmaceutical and biotech companies to work on these difficult diseases, especially those like HD, which are orphan diseases affecting relatively few patients. Our goal became a reality when MIND signed a groundbreaking agreement with Novartis; a world leader in drug discovery. The agree-
ment brings together teams from MIND, MIT and Novartis to work collaboratively on Huntingtons disease therapies. It is the first time that a large pharmaceutical company has made a substantial commitment to tackle Huntingtons disease, bringing intellectual, scientific, and financial resources to the research including Novartis formidable drug compound library. All the partners believe the collaboration will accelerate the process of finding and testing new drugs. The Hereditary Disease Foundations funding has initiated many research programs that were continued with alternate funding from the NIH or other government funding organizations, or from other charitable organizations that also support HD research, says Dr. Johnson. Given recent advances in understanding of the pathogenesis of HD in animal models, we believe that multiple new treatments for HD that have the potential to significantly impact the disease will enter clinical trials within the next 2-10 years, and that efficacious treatments for the disease will be available albeit somewhat thereafter (15-20 years). To conclude, Dr. Johnson gives a brief description of the ways to measure the progress being made in this research area. The HDF holds an annual two-day workshop of its Science Advisory Board, at which the pipeline of therapeutic opportunities, clinical trials, and progress toward understanding and validating the mechanism of the pathogenesis are critically assessed, and the research agenda for the coming years is discussed. The foundation also sponsors and organizes a large (350 scientists) biannual meeting of HD researchers worldwide that helps organize and focus research on those areas that are most relevant and promising for finding treatments and a cure for HD. By Shamsa Abdulrasak
PARKINSONS DISEASE PARKINSONS DISEASE FOUNDATION

location: New york, Ny, USA www.pdf.org
increases in the staffing and funding of their ongoing Alzheimers research programs.
ThE MCCUSKER FOUNDATION FOR AlZhEIMERS DISEASE RESEARCh, INC.

location: Nedlands, Western Australia, Australia www.alzheimers.com.au
The Parkinsons Disease Foundation (PDF) is a leading national presence in Parkinsons disease research, education and public advocacy. The foundation is working for nearly one million people in the US who live with Parkinsons by funding promising scientific research to find the causes of, and a cure for Parkinsons while supporting people with Parkinsons, their families and caregivers through educational programs and support services. Since its founding in 1957, PDF has funded over US$80 million worth of scientific research in Parkinsons disease, supporting the work of leading scientists throughout the world.
AlZhEIMERS DISEASE PACIFIC AlZhEIMER FOUNDATION

location: Vancouver, bC, Canada www.parf.ca
The mission of the Pacific Alzheimer Research Foundation is to eradicate Alzheimers disease and related dementias. It plans to support a scientific task, which will be accomplished with a generous grant of C$15 million from the Government of British Columbia and through additional fund raising activities. Scientists whose aim is to achieve this objective will be supported. The foundation will assist universities, hospitals and other qualified Canadian institutions to recruit investigators who will devote their efforts to eradicating dementia.
AlZhEIMERS RESEARCh FOR A CURE FOUNDATION

location: San Francisco, CA, USA www.arfac.org
The McCusker Foundation is a not-forprofit organization established in 2000 to enhance medical research into Alzheimers disease in Western Australia. Its aims are the identification, development of an early diagnosis, and prevention and treatments of the condition. It provides significant support to the research of the internationally recognized researcher, Professor Ralph Martins, and his team based at the Sir James McCusker Alzheimers Disease Research Unit. The Foundation sources funds from public and private sectors to advance research into Alzheimers disease and undertakes to keep the public informed on the research of Professor Martins as well as the progress of research into Alzheimers disease occurring elsewhere. To facilitate the translation of research discoveries into publicly available treatments, the foundation runs a clinical trials stream and was instrumental in the development of a private biotechnology company, Alzhyme Pty, Ltd. The foundation has a number of significant partners, such as the Hollywood Private Hospital and Edith Cowan University, both of whom provide laboratory facilities and other support for the research of Professor Martins. The foundation was also a founding partner in the development of the Centre for Excellence in Alzheimers Disease Research and Care, of which Professor Martins is the Director of Research.
drugs that slow the progression, or delay the onset of Huntingtons disease (HD). The foundation seeks to accelerate scientific progress by serving as a collaborative enabler. We encourage and support cooperation and collaboration among HD researchers. The strategy is to encourage researchers to develop practical ideas, useful research materials, and powerful technologies, often by providing financial support. The foundations activities extend from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery and development to clinical studies and trials.
MUlTIPlE SClEROSIS ChARCOT FOUNDATION

location: brussels, belgium www.charcot-ms.org
hUNTINGTONS DISEASE ChDI FOUNDATION

location: New york, Ny, USA www.highqfoundation.org
Alzheimers Research For A Cure (ARFAC) is a new non-profit, 501 (c) (3) foundation dedicated to support research into new and effective treatments for Alzheimers disease. It is their goal to provide enough additional funding to the foundations designated beneficiaries to enable them to make significant
CHDI is a private not-for-profit research organization that works with an international network of scientists to discover
The Charcot Foundation, named after the first neurologist to describe the disease, was founded in 1987 within the Groupe Belge dEtude de la Sclrose en Plaques (GBESP Belgian Multiple Sclerosis Study Group). The GBESP, a non-profit organization, was itself set up in 1957 in order to raise awareness among Belgian neurologists about the importance of multiple sclerosis and to promote the fundamental and clinical research necessary to combat the progression of the disease. The foundation exclusively supports fundamental and clinical research aimed at treating the disease. The foundations assets, built over several decades in accordance with its mission and goals, enable the foundation to provide substantial grants to Belgian researchers every year. In 2001, the Charcot Foundation was officially recognized as a public interest foundation. Since its creation, the foundation has relied on the help of the world of culture and of numerous volunteers who generously share their talents and time. The foundation also relies on the support of official institutions and private companies and regularly receives gifts and bequeathals that contribute to its overall fund. Gathering these resources, which are essential to research, is one of the principal aims and concerns of the Charcot Foundation. To fulfill this aim, a number of fund-raising projects are currently under way.
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Saint and Sinner by Keith Russell All rights reserved. www.redbubble.com/people/affectmachine
GLOBAL FOUNDATION
NEURODEGENERATION
fondation Andr Delambre www.fondationandredelambre.com Laval, Canada
Alzheimers Drug Discovery foundation www.alzdiscovery.org New York, NY, USA cHDi foundation www.highqfoundation.org New York, NY, USA
pacific Alzheimer research foundation www.parf.ca Vancouver, Canada
Hereditary Disease foundation www.hdfoundation.org New York, NY, USA parkinsons Disease foundation www.pdf.org New York, NY, USA
Alzheimers research for a cure foundation www.alzheimers researchforacure.org San Francisco, CA, USA Myelin repair foundation www.myelinrepair.org Saratoga, CA, USA
THE MAP PROVIDES A NON-EXHAUSTIVE GLOBAL VIEW OF SOME OF THE MAJOR FOUNDATIONS SUPPORTING RESEARCH ON NEURODEGENERATIVE DISEASES. THESE FOUNDATIONS REPRESENT THE FUNDING INITIATIVE INTO NEURODEGENERATIVE RESEARCH ACROSS THE WORLD.
nancy Davis foundation for Multiple sclerosis www.erasems.org Los Angeles, CA, USA the John Douglas french Alzheimers foundation www.jdfaf.org Los Angeles, CA, USA
neuro challenge foundation www.neurochallenge.org Sarasota, FL, USA
Alzheimers research foundation www.alzheimers-research.org Virginia Beach, VA, USA
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Alzheimers research trust www.alzheimers-research.org.uk Cambridge, UK Ms research www.ms-research.org.uk Bristol, UK
fondation pour la recherche Mdicale www.frm.org Paris, France
european charcot foundation www.charcot-ms.org Brussels, Belgium
german Multiple sclerosis foundation www.dmsg.de Hannover, Germany
neurological foundation of new zealand www.neurological.org.nz Auckland, New Zealand
foundation la caixa www.fundacio.lacaixa.es Barcelona, Spain
parkinsons Disease foundation of india www.parkinsons diseaseindia.com Mumbai, India
the Mccusker foundation for Alzheimers Disease research www.alzheimers.com.au Nedlands, Australia
nerve research foundation www.nrf.med.usyd.edu.au Sidney, Australia
INDUSTRY
NEURODEGENERATION
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NEURODEGENERATIVE MARKET SPACE
onfronting neurodegenerative diseases represents an impressive challenge for our ageing society. The World Health Organisation has predicted neurodegenerative diseases to overtake cancer and become the worlds leading cause of death by 2040. There is a lack of, and a huge medical need for further treatment options. Development of new therapies having just marginal efficacy leaves room for enormous revenues and a blockbuster in terms of sales. With the worlds population living longer, the disease prevalence will increase. This will result in a drug market worth billions; expected to double in size in the coming decade. Companies investing in and developing successful and innovative new treatments that may improve quality of life for patients stand to make a fortune. The current treatments available for neurodegenerative diseases are symptomatic and do not affect the underlying course of the disease. The causes and mechanisms of action are not fully understood, which has led to a lack of drugs that adequately address these diseases. There is, therefore, a large unmet medical need for drugs that delay the onset of these diseases, or retard disease progression and restore normal function. Emerging therapies include stem cell treatment, gene therapy and monoclonal antibodies, in addition to novel delivery strategies that have an important role in the transfer of central nervous system (CNS) therapeutics from bench-to-bedside.
Alzheimers Disease
According to a study, AD affects approximately 30 million people worldwide, and is projected to hit over 100 million in 2050. Over 60% live in developing countries and this number is expected to rise to 71%. The fastest growing demographic area is Asia, and this market segment is expected to increase dramatically in the coming years, in particular China, India and South East Asia. Direct and indirect annual costs of AD and other forms of dementia in the US are around US$150 billion. Worldwide, costs for dementia care are estimated at US$315 billion per year. Despite significant research into this disease, advances in the development of diagnostic tests for AD and, moreover, effective treatments remain elusive. Approximately US$5.5 billion were spent on the symptomatic treatment of AD in 2007. The majority of this revenue was generated by just four drugs within two main classes. However, as a number of the main AD drugs face patent expiry within the coming years, this will have a considerable impact on the profits of the companies involved. A significant change in the AD market is projected by 2014 due to increased generic competition, improved use of acetylcholinesterase inhibitors, and new product launches that will treat the condition and not the symptoms. Driven by the launch of disease modifying treatments and an expanding patient population, the AD market is foreseen to double over the next 10 years. A number of late-stage pipeline products hold blockbuster potential; however, the risk of clinical trial failure remains high. It is unlikely that a treatment will be developed which completely halts, or reverses, the cognitive decline observed in AD over the 10 year time horizon. A symptomatic market will remain for this disease over the forecast period. The main trends in the AD market are an increase in the number of patients suffering from the disease as the population ages, as well as drugs used earlier in therapy. It may be some time before the first diseasemodifying agents emerge that could revolutionize the way AD is treated. Companies: Neuron BPh, AFFiRiS, Baxter, Novartis and Cytos Biotechnology, Eli Lilly, Genentech and AC Immune, GlaxoSmithKline, Merck & Co., Octapharma, Pfizer, Roche
and MorphoSys, Wyeth and Elan, Shire Pharmaceuticals, Eisai, Merz, Lundbeck, Forest Laboratories, and Johnson & Johnson Products and Technologies: Stem cell therapy, hormone therapy, medications, Aricept, Bapineuzumab, Ebixa, Namenda, Exelon, Razadyne, Reminyl, and DBS
Eli Lilly, Endo Pharmaceuticals, EnVivo, Janssen, MethylGene, NeuroSearch, Novartis, Pfizer, Prestwick Pharmaceuticals, Renovis, Sanofi -Aventis, Wyeth, Prestwick, Cambridge Laboratories, and NeuroSearch Products and Technologies: Stem cell therapy, gene therapy, neurotrophic enhancers, speech therapy, physical and occupational therapy, medications, Miraxion, HD-02, Xenazine, and ACR-16
huntingtons Disease
HD affects only a small part of the worldwide population and no drug is approved for treatment leaving a huge gap in the market. As no therapies are available specifically for HD, the current therapies are used offlabel and provide only symptomatic relief. In the short term, two pipeline drugs are set to enter the market, demonstrating the viability of this disease as a primary marketing indication. In the longer term, with a strong genetic link and reliable diagnostic test, prophylactic treatment with a disease modifying drug could prove lucrative. Other treatment approaches for HD that may bring some market changes include further research developments in stem cell transplantation (disease-modifying stem cell therapy) and gene therapy. Commercial opportunity abounds, but the small patient population deters some companies. However, because of novel treatment approaches, interest in HD research is growing and companies may be able to tap into the enormous commercial potential, especially if a drug can treat multiple neurological diseases. For the common neurodegenerative conditions, there is tremendous incentive to develop new therapies. A novel therapy will be a blockbuster in terms of sales. In contrast, the relatively small number of patients with a rarer neurodegenerative disease, such as HD, means there is less commercial interest in developing new therapies. Thus, most therapeutic development for these conditions takes place in academic laboratories with an increasing effort from philanthropic organizations to assist with the clinical development. Occasionally, biotech companies or major pharmaceutical companies will partner in these efforts, but typically with limited resources. Companies: Abbott, Amarin, Amgen, AstraZeneca, Avicena, Bristol-Myers Squibb, Carlsson Research, Ceregene, Edison Pharmaceuticals,
Parkinsons Disease
PD is a progressive, degenerative condition of the central nervous system. In the absence of conclusive evidence for a neuroprotective compound, the focus on the market for this disease lies also on symptomatic treatment. In 2007, nearly US$3.6 billion were spent on symptomatic treatments of this disease. Manufacturers of neuroprotective products will benefit from driving research and awareness of new diagnostic technologies, such as genetic testing to better identify patients in the very early stages of PD or those at risk of the disease. The PD market value is set to grow by a compound annual growth rate of 10% until 2013 and to peak at around US$3.1 billion. Companies who are set to increase their revenue are those developing improved delivery technologies. These companies will be at a competitive advantage and novel formulations will prove to be an increasingly important product differentiating strategy. An unmet need in the treatment in advanced PD is the reduction of off-periods. Few companies have investigated this area since advanced patient opportunities represent a very small market and presently there is only one drug available for this specific use. Over the coming five years, many of the leading dopamine agonists for treating PD face patent expiry. Generics will become freely available and a number of companies have such treatments in the pipeline. In addition, new disease-modifying agents are being developed that could revolutionize the treatment through halting the progression of the disease. Companies: Teva Pharmaceuticals, Lundbeck, GlaxoSmithKline, UCB, Boehringer Ingelheim,
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Novartis, Orion, Kyowa Hakko, UCB, Solvay, Merck Serono, Bayer, Titan Pharmaceuticals, Ipsen, and Britannia Pharmaceuticals Products and Technologies: Stem cell therapy, DBS, neuro-rehabilitation, gene therapy, light therapy, music therapy, medications, Sifrol, Stalevo, Requip, Apokyn, Azilect, Comtan franchise, Istradefylline, Mirapex, Neupro, Pardoprunox, Safinamide, and Spheramine
Products and Technologies: Medications, Rilutek, Neurontin, physical, occupational or speech therapy, anti-drooling medications, anti-anxiety drugs and antidepressants, pain medication, and insomnia medications
bSE Creutzfeldt-Jacob Disease (Prion Diseases)

Prion diseases, such as Creutzfeldt-Jacob, remain a minor segment in the neurodegenerative market space. Currently, there is no known cure for prion diseases. Standard approaches have proven ineffective or even dangerous due to an inability of the compounds to cross the blood brain barrier and possible toxic side effects. The main market segment for prion diseases is that of test kits. The annual market for post-mortem transmissible spongiform encephalopathy (TSE) test kits exceeds US$100 million. This market consists primarily of Europe and Japan; for example, the US does not conduct many TSE tests despite large cattle populations. The level of post-mortem testing for TSE diseases in North America is, however, expected to increase. Growth of prion testing will depend on technology breakthroughs and the future prevalence of prion disease. Post-mortem TSE testing is widespread, but growth will vary with disease prevalence and outbreaks in coming years. The sensitivity and specificity of detection technology are the main forces driving postmortem and ante-mortem technology development. While concerns have been expressed regarding the ethics of identifying infected individuals when the means to treat them are lacking, there is a need to prevent infection through blood transfusions. Significant market opportunities are envisioned in the testing of, e.g., donor blood. Companies: Adlyfe, Idexx Laboratories, Prionics AG, Microsens Biotechnologies, Biotraces, Inc., Caprion Pharmaceuticals, Inc., Chronix Biomedical, Gene Thera, and VMRD, Inc. Products and Technologies: Screening test for PrPsc, Bionconformatics, MultiPhoton Detection (MPD), and CellCarta With an increase in lifespan and changing population demographics, the prevalence of neurodegenerative disorders is expected to increase significantly in the 21st century. Due to a huge unmet medical need, the ageing of the baby-boom generation, and a dynamic and highly promising product pipeline, the market sector is highly lucrative for biotechnology and pharmaceutical companies worldwide, but potentially devastating for most societies. By Johanna Reichen
Multiple Sclerosis
MS is an autoimmune condition affecting an estimated 2.5 million people worldwide. The prevalence rate of MS is the highest in Canada, closely followed by the US. Other countries with high prevalence rates are Germany, Norway and Hungary. MS is also slowly spreading to Asian regions and these will form a potential market in the future. In 2008, the MS treatment market showed good results despite the slowdown of the US segment. This success has increased the probability for future world market growth. Only a handful of companies dominate the MS market. Of the worlds MS patients, approximately 35% are currently being treated with MS drugs and the percentage is expected to increase to 55% within the coming 6 years as new oral therapies are introduced. The market for injectable drugs is huge but their side effects may cause a shift to oral medications. The worlds MS market was estimated at US$8 billion in 2008 with an approximate annual growth rate of 10%. The oral agents launched, or soon to be, will have a considerable affect on the market and in the way MS patients are treated. In addition, vaccines are being developed; each with a unique approach to targeting the disease. The MS market is in a phase of evolution and the many new treatment options have potential to improve the quality of life for a large number of patients. Companies: Biogen Idec, Teva Pharmaceuticals, EMD Serono, Bayer Schering Pharma, Elan Corporation, Merck Serono S.A., Novartis, Acorda Therapeutics, Biogen, Eli Lilly, BioMS Medical, Teva Pharmaceuticals, Bayer, SanofiAventis, and Acorda Therapeutics Products and Technologies: Medications, Campath, BG12, Dirucotide, Fingolimod, Neurelan, Avonex, Copaxone, Rebif, Betaferon, Lacquinimod, MBP 8298, Mylinax, Teriflunomide, and stem cell treatment
Amyotrophic lateral Sclerosis

ALS is a rapidly progressing motor neuron disease. Approximately 120,000 cases are diagnosed each year and a cure has yet to be found. There is currently only one drug, called Riluzole, that modestly slows the progression of the disease and several other drugs are used to treat the symptoms. The worlds ALS market was worth US$148 million in 2006. By 2012, the market will face generic drug entry and future growth is dependent on the success of pipeline drugs. Commercial development in ALS has been minimal, as companies are discouraged due to the limited understanding of the mechanisms of the disease and the small patient population. In addition, past failures of promising agents have re-emphasized the need for large trials to provide sufficient efficacy and safety data for emerging ALS treatments, which causes financial and operational challenges for companies considering market entry. Nevertheless, the high unmet treatment need and the orphan status of ALS offers numerous financial, marketing, and drug-approval benefits. There is a substantial opportunity for any company developing an efficacious agent to treat the disease. Current research projects include the development of small molecules, peptides, proteins, antibodies, vaccines, as well as cells for treating this disease, and emerging therapies use antiglutamatergic agents, antioxidants, the induction of heat shock proteins, and neurotrophic factors. Some other emerging trends in the treatment of ALS include non-invasive positive pressure ventilation and stem cell therapy. Companies: Sanofi-Aventis, BrainStorm Cell Therapeutics Inc., Aeolus Pharmaceuticals, Cephalon, Chiron, and CytRx Corporation
IMPROVING ThE EFFICIENCy OF CNS DRUG DISCOVERy

by Katherine Tsaioun
The costs of drugs failing in clinical development or when they are already on the market is the greatest source of economic waste in the pharmaceutical industry (Kaitin, 2008). According to the Tufts Center for the Study of Drug Development, the average cost of getting a drug onto the market is approaching US$1 billion, and the cost of advancing a compound to phase I trials can reach up to US$100 million. Each day a drug is in the development stage incurs US$37,000 in direct out-of-pocket costs, and represents opportunity costs of US$1.1 million in lost revenue (DiMasi et al., 2003). Starting in the mid-1990s, a series of technological advances allowed in vitro testing of prospective drug candidates to assess their ADMET, or drug-like, properties. ADMET is an acronym for absorption, distribution, metabolism, excretion and toxicity, and refers to issues about how chemicals behave in the body. For example, these tests can determine if a chemical, when turned into a pill, would be absorbed through the intestinal tract, and what sort of metabolic transformations it may undergo as it goes through different organ systems on the way to the target tissue. ADMET testing has now proven success at eliminating poor drug candidates from further development, doing so at a fraction of the cost of identifying the same problems in clinical trials (Kola and Landis, 2004).
Katherine tsaioun, Ph.D., is the CEO and CoFounder of Apredica, a contract research laboratory specializing in ADMET testing. Before founding Apredica, Dr. Tsaioun managed preclinical ADMET programs in a number of pharmaceutical companies. She received her Ph.D. in Biochemistry from Tufts University and completed post-doctoral work in neurochemistry at Harvard University. She is a frequent speaker on ADMET at scientific conferences and a member of the Scientific Review Board for the Alzheimers Drug Discovery Foundation and the International Rett Syndrome Foundation. katya@apredica.com
Unique Problems of Developing Central Nervous System Drugs The purpose of pre-clinical lead optimization and clinical candidate selection activities is to eliminate weak candidates and select candidates with drug-like properties as early as possible. This allows drugdevelopment resources to be focused on fewer, but more-likely-to-succeed, drug candidates. In 1993, 40% of drugs failed in clinical trials because of pharmacokinetics (PK) and bioavailability problems (Kaitin, 2008). Since then, major technological advances have occurred in molecular biology and screening, to allow major aspects of ADMET to be assessed much earlier than was possible before. By the late 1990s, the pharmaceutical industry as a whole recognized the value of early ADMET assessment and began routinely employing it. The results were striking. Drug metabolism and pharmacokinetics reasons for failure fell from 40% to 11% (Kola and Landis, 2004). In most successful programs, ADME is now an important part of the overall drug-discovery cascade. ADME screening is started at the late discovery stage, implemented in hit selection, and hit-to-lead and leadoptimization phases of the drug discovery process. Now, the largest sources of failure are lack of efficacy and unexpected toxicity (Kola and Landis, 2004). A prime determinant of both issues is how easily can a drug get to the biological target. Hence, it is crucial to understand how the drug penetrates biological barriers, such as the cell membrane, intestinal wall, or blood-brain barrier (BBB). This is especially true for central nervous system (CNS) drugs, because candidates that have in vitro efficacy but cannot penetrate the BBB to reach targets in the brain are unlikely to be of clinical benefit. Making the problem even more difficult, specific metabolizing enzymes and efflux pumps, such as P-glycoprotein (P-gp) and the multi-drug-resistance protein (MRP), located within the endothelial cells, actively remove exogenous molecules from the brain (Liu and Chen, 2005). Hence, it is no coincidence that CNS drugs under development have a notoriously high failure rate (Hurko and Ryan, 2005). In recent years, only 9% of the compounds that entered phase I survived to launch, and only 3-5% of CNS drugs made it onto the market (Hurko and Ryan, 2005).
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RefeRences
Begley, D. J., Lechardeur, D., Chen, Z. D., Rollinson, C., Bardoul, M., Roux, F., Scherman, D., and Abbott, N. J. (1996). Functional expression of Pglycoprotein in an immortalised cell line of rat brain endothelial cells, RBE4. J. Neurochem. 67, 988-995. Deli, M. A., Abraham, C. S., Kataoka, Y., and Niwa, M. (2005). Permeability studies on in vitro blood-brain barrier models: physiology, pathology and pharmacology. Cell. Mol. Neurobiol. 25, 59-120. Di, L., Kerns, E. H., Bezar, I. F., Petusky, S. L., and Huang, Y. (2009). Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1MDCKII and PAMPA-BBB. Pharm. Sci. 98, 1980-1991. DiMasi, J. A., Hansen, R. W., and Grabowski, H. G. (2003). The price of innovation: new estimates of drug development costs. J. Health Economics 22, 151-185. Hurko, O., and Ryan, J. L. (2005). Translational research in central nervous system drug discovery. NeuroRx 2, 671-682. Kaitin, K. I. (2008). Obstacles and opportunities in new drug development. Clin. Pharmacol. Ther. 83, 210-212. Kola, I., and Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711-715. Liu, X., and Chen, C. (2005). Strategies to optimize brain penetration in drug discovery. Curr. Opin. Drug Discov. Dev. 8, 505-512. Megard, I., Garrigues, A., Orlowski, S., Jorajuria, S., Clayette, P., Ezan, E., and Mabondzo, A. (2002). A co-culture-based model of human blood-brain barrier: application to active transport of indinavir and in vivo-in vitro correlation. Brain Res. 927, 153-167.
Failure to demonstrate efficacy in phase II studies was responsible for over half of this attrition. Over the past decade, phase II failures have increased by 15%. Compounds with demonstrated efficacy against the target in vitro and in animal models have more often than not lacked efficacy in human clinical trials. Given the extraordinary development costs and high failure rate for CNS drugs, it is highly desirable to have effective, costefficient tools to measure BBB permeability before proceeding to more expensive studies. Further, if such tools were available, promising drug candidates without effective BBB penetration could be improved at the earliest stages of development to increase intrinsic permeability. A number of in vivo and in vitro approaches have been proposed and proven to provide incremental useful information (Deli et al., 2005). The standard in the industry is in vivo mouse or rat brain penetration and in situ brain
perfusion. Although these methods have a relatively good correlation with human BBB permeability with regard to passive and P-gp-influenced BBB permeability, this approach is low-throughput and has shown to have differences with human BBB with regard to some transporters (Di et al., 2009). Among common in vitro BBB assays are artificial membrane permeability assays (PAMPA), and cell-based assays with over-expressed transporters, most commonly, P-gp, and co-culture systems (Di et al., 2009). Each has significant drawbacks that prevented them from becoming industry norm, so, normally, pharmaceutical companies implement a number of approaches in a funnel fashion appropriate for different stages of drug discovery programs, such as hit validation, hit-to-lead, lead optimization and pre-clinical candidate characterization. PAMPA assays only predict passive permeability of compounds and cannot detect active efflux out of the brain or import of drugs into the brain,
but can be very high-throughput and are useful at the level of hit validation, if a program starts out with a lot of compounds. Cell-based assays, such as MDCK cells over-expressing P-gp, may over-predict the role of efflux due to higher levels of P-gp in this model compared to endogenous expression of this transporter, and also do not take into account the interaction with other BBB transporters (Begley et al., 1996). Human and bovine co-culture cell models have been notoriously non-reproducible. Recently, a co-culture model based on human brain cells was described that has promising results (Megard et al., 2002). Hence, given the level of interest, economical need and resulting research activity in this area, in the foreseeable future we can look forward to not only a decrease in late-stage development failures and withdrawals of marketed drugs, but also faster timelines from discovery to clinic to market, and reduced development costs through the reduction of late-stage failures.
INDUSTRY HIGHLIGHTS
NEURODEGENERATION
ARTIEllE IMMUNOThERAPEUTICS
Artielle ImmunoTherapeutics, Inc., is headquartered in Portland, OR, US. It is a clinical stage biopharmaceutical company in possession of a platform technology for inflammatory diseases. The core technology, which has generated a novel proprietary class of molecules (i.e., recombinant T-cell receptor ligands (RTLs)), can be customized to treat a range of autoimmune diseases. The company recently completed a phase 1 clinical safety trial for a leading drug candidate, RTL1000, for multiple sclerosis. The technology platform of Artielle is the subject of an exclusive worldwide license from the Oregon Health & Science University and protected by multiple US and foreign patents and patent applications.
www.artielle.com
Fampridine-SR, improves walking ability in persons with multiple sclerosis and its Zanaflex capsules help manage spasms.
www.acorda.com
ANAVEX lIFE SCIENCES, CORP.

ANAVEX Life Sciences Corp. is a biopharmaceuticals company based in Geneva, Switzerland. The company engages in the discovery and development of new drugs for the treatment of neurological diseases and cancer, through its proprietary drug discovery SIGMACEPTOR platform. The companys lead drug candidates exhibit high affinity and selectivity to sigma receptors and also synergistic action with other receptors, such as muscarinic and NMDA, with strong evidence of anti-amnesic, neuroprotective, and anxiolytic properties. ANAVEX 2-73, which targets Alzheimers, is one of the companys leading drug candidates and expected to enter its first clinical trials this year.
www.anavex.com
OPEXA ThERAPEUTICS
Opexa Therapeutics is a biotechnology company based in the Woodlands, TX, US, dedicated to the development of patientspecific cellular therapies for treatment of autoimmune diseases, such as multiple sclerosis and diabetes. The companys product candidates have the potential to offer enhanced efficacy, safety and tolerability to address the significant unmet medical needs in several large patient populations. Opexas lead product is Tovaxin, a novel T-cell vaccine for the treatment of MS that is specifically tailored to each patients disease profile.
www.opexapharmaceuticals.com
EXONhIT ThERAPEUTICS
ExonHit is a fast emerging healthcare player developing innovative molecular diagnostic tests and therapeutics for neurodegenerative and cancer indications. The company focuses on the exploitation of alternative RNA splicing to identify new therapeutic targets and blood biomarkers. In December 2009, the company launched its first product - AclarusDx Alzheimers test - the first blood-based test to select or stratify patients suffering from Alzheimers disease in clinical research.
www.exonhit.com
ACORDA ThERAPEUTICS
Acorda Therapeutics is a biotechnology company based in Hawthorne, NY, US, engaged in the identification, development and commercialization of novel therapies that restore neurological function in people with multiple sclerosis, spinal cord injury, and related conditions of the nervous system. The companys lead product,
APPlIED NEUROSOlUTIONS
Applied NeuroSolutions is a development stage biotechnology company based in Vernon Hills, IL, US. The company focuses on the research and development of products for the early diagnosis and treatment of Alzheimers disease. The company works on
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a cerebrospinal fluid based test and a serum based test to detect early stage Alzheimers. The core technology of the company is based on licences with Albert Einstein College of Medicine covering all diagnostic and therapeutic applications in the area of neurodegenerative diseases.
www.appliedneurosolutions.com
PICO-TESlA
Pico-Tesla is an emerging medical technology company based in Littleton, CO, US. The companys Magneceutical therapy involves the use of an extremely low-level electromagnetic field applied by a specially designed device, the Resonator, along with proprietary therapeutic protocols, intended to improve a number of the signs and symptoms of Parkinsons and other neurological-based diseases. The magneceutical therapy is generally not available outside investigational review board approved clinical studies.
www.picotesla.com
pany develops technologies focused on the diagnosis and treatment of neurodegenerative disorders. Amorfix is dedicated to becoming the world leader in the diagnosis and treatment of aggregated misfolded protein diseases of the brain, such as bovine spongiform encephalopathy and the human form variant Creutzfeldt-Jakob disease, as well as degenerative diseases, such as Alzheimers, amyotrophic lateral sclerosis and Parkinsons disease.
www.amorfix.com
MEDIVATION, INC.
Medivation, Inc., is a biopharmaceutical company based in San Francisco, CA, US. The company engages in researching and developing small molecule drugs for the treatment of Alzheimers and Huntingtons disease, and hormone-refractory prostate cancer. Dimebon, the lead product candidate, is an investigational compound currently in phase 3 development for the treatment of Alzheimers and Huntingtons disease. In pre-clinical studies, dimebon has been shown to protect brain cells from damage and enhance brain cell survival, potentially by stabilizing and improving mitochondrial function. Medivation is currently evaluating dimebon with its partner Pfizer, Inc., in clinical trials for both Alzheimers and Huntingtons disease. In order to support a broad and differentiated label, Medivation and Pfizer have expanded their Alzheimers phase 3 clinical development program to include five new trials.
www.medivation.com
AFFIRIS
Affiris is an innovative biotechnology company based in Vienna, Austria. Using its proprietary AFFITOME-technology, it is able to develop customised peptide-based vaccines targeting Alzheimers and Parkinsons disease, atherosclerosis and other diseases with unmet medical needs. Based on its business model and its globally unique expertise, Affiris aims to initiate the clinical testing of a new vaccine against thus-far incurable diseases every two to three years.
www.affiris.com
POWER3 MEDICAl PRODUCTS, INC.

Power3 Medical Products, Inc. is situated in Woodlands, TX, US. The company is a leading biomedical company engaged in the commercialization of neurodegenerative disease and cancer biomarkers, in pathways and mechanisms of diseases through the development of diagnostic tests, and drug targets. Power3 Medicals patent-pending technologies are being used to develop screening and diagnostic tests for the early detection and prognosis of disease, and the identification of protein biomarkers and drug targets. Diagnostic tests are targeted toward markets with critical unmet needs in areas including neurodegenerative disease (NuroPro).
www.power3medical.com
NEURAlSTEM, INC.
Neuralstem, Inc., is a biotechnology company based in Rockville, MD, US. The company uses its human neural stem cell technology to create biotherapeutic products for the treatment of central nervous system diseases and various neurodegenerative conditions, such as ALS and Parkinsons, and for the regenerative repair of acute diseases. Its proprietary technology is also used in small-molecule drug discovery. Neuralstems patent-protected human neural stem cell technology allows the production of mature, commercial quantities of neural stem cells with the ability to control the differentiation of the cells into physiologically relevant human neurons and glia. When approved by the FDA, these cells could be transplanted into humans as treatments for currently incurable diseases.
www.neuralstem.com
ENVIVO PhARMACEUTICAlS
EnVivo Pharmaceuticals is a biopharmaceutical company headquartered in San Diego, CA, US. The company is dedicated to discovering and developing drugs for central nervous system disorders with an emphasis on cognitive and neurodegenerative disorders. Currently, the focus lies on Alzheimers disease and schizophrenia. The companys lead programs include a nicotinic -7-acetylcholine receptor agonist program for cognitive enhancement in Alzheimers and schizophrenia, a histone deacetylase (HDAC) inhibitor program for cognitive enhancement in Alzheimers disease, a -secretase modulator (GSM) program for disease modifying treatment of Alzheimers disease, and a phosphodiesterase-10 (PDE10) program for schizophrenia.
www.envivopharma.com
AMORFIX lIFE SCIENCES

Amorfix Life Sciences is a theranostics company based in Mississauga, ON, US. The com-
ON THE HORIZON
NEURODEGENERATION
ENGINEERED VIRUS TREATS AlZhEIMERS

Entering phase 2 scientific trials, CERE-110, a virus injected directly through surgically drilled holes into parts of the brain affected by Alzheimers disease, shows promise. The therapy could halt and possibly even reverse dementia by boosting the nerve growth factor (NGF) gene to express this growth factor protein.
brains. It is expected that in the future it will be possible to treat patients suffering from diseases, such as Parkinsons, using this technique to stimulate the brain. One question remains open though; what happens when the nanoelectrodes break off from their contact points.
bODy TURNS CEllS INTO ARTIFICIAl STEM CEllS

In a recent study, scientists have been able to complete the transformation of regular body cells into stem cells without having to introduce foreign DNA material. In order to regenerate the eyes cornea, progenitor eye cells were sampled from laboratory rats. By reprogramming the cells to resemble stem cells, these cells acquired the properties needed to replace or restore neurons, hepatocytes and cardiomyocytes that are degenerated in, for example, Parkinsons disease.
hElP TO TRACK AlZhEIMERS PATIENTS

Through a US$185 purchase and a US$25 monthly service charge, you can keep track of your grandmother or other persons suffering from Alzheimers or other cognitive or developmental disorders. EmFinders, a US based start-up, has launched its EmSeeQ, which is worn like a watch and works with cellular network technology (U-TDOA) to provide information to alert law enforcements and emergency systems if someone goes astray.
AlZhEIMERS VACCINES
AFFiRiS AG have announced that its two vaccines for Alzheimers , AD01 and AD02, have demonstrated favorable tolerability and safety profiles. The company is using the same AFFITOME(R) technology to also develop vaccines for Parkinsons.
blOOD TEST TO DETECT bSE

Amorfix Life Sciences is developing a blood test for detecting prions present in BSE infected persons or cattle. The test may be used by transfusion services, cattle ranchers, and companies who produce cosmetics, pharmaceuticals and medical devices from sources that may contain the virus.
GENES CORRECT MOTOR DEFECTS

A new potential gene therapy to treat Parkinsons disease has shown promising results in monkeys. Motor deficits were corrected using the medication without causing any jerky or involuntary movements.
ElAN MAKES EXCEPTIONAl ONE-OFF PROFIT

Elan Corp. PLC has reported an exceptional gain after its one billion dollar agreement with Johnson & Johnson. The joint venture to develop drugs to treat Alzheimers has given Elan a profit of US$107.7 million in the third quarter of 2009.
AlNylAM AND MEDTRONIC RElEASE DATA FROM hUNTINGTONS PROGRAM

Alnylam Pharmaceuticals and Medtronic are collaborating to develop a drug-device combination to fight Huntingtons disease. ALN-HTT targets huntingtin through an sRNAi therapeutic and can be broadly distributed to the CNS when administered directly and continuously.
DIGITAl TEChNOlOGy TO FIGhT AlZhEIMERS

Microsoft has developed SenseCam, a device to be worn by patients suffering from Alzheimers. The cognitive prosthetic will record data in a number of different ways during outings and thereby perhaps aid patients to jog their memory.
MIlK TOOTh CEll bANKING

You can now collect and preserve stem cells with BioEDEN through milk tooth banking. The company collects, assesses and cryogenically stores living tooth cells from milk teeth for future treatments. Many researchers believe that stem cells hold the
NANOWIRES IN RAT bRAINS

Researchers at the University of Lund in Sweden have for the first time managed to successfully carry out experiments involving the injection of nanowires into rat
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best potential to treat neurodegenerative disorders, such as Alzheimers, Parkinsons and Huntingtons.
disease. The small size and longevity of the battery is a real improvement for patients.
ID ChIPS IN AlZhEIMERS PATIENTS

There is a controversy in the US about Verichip Corp.s plan to implant ID chips into 200 Alzheimers patients living in Florida over the next two years. The involved hope that the chips will help in keeping the patients safe by allowing a faster location of missing AD patients.
SOFTWARE TO DETECT EARly MS

Researchers at the University of Jan, Spain, are developing a software to detect early stage MS before the typical brain damage has appeared. MRI images are used to calculate the fractal dimension of the brain. In the future, the technique will also be used to detect other neurodegenerative disorders.
PARKINSONS PATIENTS SPEAK lOUDER

Patients of Parkinsons often suffer from speech problems. A new technology may help patients overcome their tendency to speak quietly by playing ambient sounds resembling a noisy restaurant. The background sounds elicit the Lombard effect and patients automatically speak louder.
DRUGS TO MARKET
Dr. Howard Fillet (Alzheimers Drug Discovery Foundation) presented sobering statistics at the 2009 Conference on Drug Discovery for Neurodegeneration. 90% of research is on drugs that do not come to market. Out of 10 drugs that are approved, only 3 are applied in clinical settings and of these only one will generate profits.
NASA AlGORIThM PATENT SOlD

DynaDx Corporation of Mountain View, CA, US, has obtained exclusive rights to HHT, a technology developed by NASA, which is used to improve the diagnosis, as well as the treatment, of brain conditions. The rights were transferred at the first ever sale of a government-owned patent licence in a public auction of IP.
SIDE EFFECTS OF DEMENTIA DRUGS

Cholinesterase inhibitors prescribed to improve brain function and preserve memory have the opposite effect on a subset of people as reported by Canadian and US researchers. Other side effects include fainting, slowed heart-rate and the necessity to implant pacemakers.
MS MARKET GROWTh
According to a US market analysis, the market for MS treatment has been growing from US$4.4 billion in 2005 to nearly $6 billion in 2007. Until 2011, further growth of up to $11.9 billion is expected. This growth will be partly due to new developments and improved formulations of existing treatments, but also due to the rising rate of patients all over the world.
RISKy ShORT-TERM USE OF ANTIPSyChOTICS

Antipsychotic drugs are used to treat agitation as a behavioral and psychological symptom of dementia. Patients who receive these medications (like olanzapine, quetiapine fumarate and risperidone) are more often hospitalized, or even die, than those that had not taken these drugs.
AlZhEIMERS TEST
Applied NeuroSolutions, Inc., a biotechnology company that develops products for the diagnosis and treatment of early Alzheimers, has confirmed that, based on its research development, sufficient analytical sensitivity has been achieved to detect tau in serum samples of patients. The success is a key factor in the further development of blood-based tests to detect early stage Alzheimers.
NEW DIAGNOSIS FOR AlZhEIMERS DISEASE AND DEMENTIA

Early diagnosis is important to treat dementia effectively and slow the progression of the disease. Positron Emission Tomography (PET) imaging allows classification of types of dementias with higher success rates than other diagnosis tools.
NOVARTIS ANNOUNCES MS ThERAPy

Novartis will present comprehensive data on the MS treatment FTY720 in 2010, but already announced that the oral drug impacts disability progression as well as relapses. Relapsing-remitting multiple sclerosis is one of the most common causes of neurological disability.
MAGNETIC ThERAPy TO TREAT PARKINSONS

Pico-Tesla has announced that it has started a Phase 3 clinical test series of the patented Resonator system in order to facilitate the companys proprietary Magneceutical therapy. The aim is to prove the efficacy of its magnetic therapy as an adjunctive therapy in treating Parkinsons.
NEW MS DRUG hAS ThE POTENTIAl TO SAVE ThE NhS 300 MIllION PER yEAR
The Low Dose Naltrexone (LDN) Research Trust claims that the drug could significantly improve the lives of 100,000 MS patients in the UK, and save the NHS 300 million per year. LDN is FDA approved for treatment of alcoholism and drug addiction. Since LDN is a generic drug, the research trust is now campaigning to find pharmaceutical companies interested in funding trials to approve the drug for MS treatment.
VOlUMETRIC MRI PREDICTS DETERIATION

Scientists at the University of California, San Diego School of Medicine, used NeuroQuant, a fully automated volumetric MRI system developed by CorTechs Labs that can predict the progression from mild cognitive impairment (MCI) to Alzheimers disease (AD). Neurologists can identify those MCI patients that will develop AD, and treatments targeted to prevent or slow down neurodegeneration can be started immediately.
WORlDS SMAllEST, REChARGEAblE DEEP bRAIN STIMUlATOR FOR PARKINSONS DISEASE

St. Jude Medical, Inc., has received the CE Mark approval for its Brio neurostimulator. It is the smallest, longest-lasting rechargeable DBS device in the world used for treating the symptoms of Parkinsons
For resources and references visit www.frontiersin.org/ neuroscience
GLOBAL INDUSTRY
NEURODEGENERATION
bioMs Medical Therapeutic technologies www.biomsmedical.com Edmonton, Canada
transgenomic, inc. Diagnostics www.transgenomic Omaha, NE, USA
biovail Pharmaceuticals www.biovail.com Mississauga, Canada
Airmid, inc. Pharmaceuticals www.airmid.com Redwood City, CA, USA Avicena group Biotechnology and pharmaceutical programs www.avicenagroup.com Palo Alto, CA, USA
isis pharmaceuticals Antisense drug technology www.isispharm.com Carlsbad, CA, USA Acadia pharmaceuticals Biopharmaceuticals www.acadia-pharm.com San Diego, CA, USA Alnylam pharmaceuticals RNAi technology www.alnylam.com Cambridge, MA, USA biovista, inc. Drug research www.biovista.com Charlottesville, VA, USA eMD serono Biopharmaceuticals www.emdserono.com Billerica, MA, USA
180 | December 2009 | Volume 3 | Issue 3
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cambridge laboratories Pharmaceutical products www.camb-labs.com Dublin, Ireland elan Biopharmaceuticals and drug technologies www.elan.com Dublin, Ireland
bioeDen Stem cell therapy www.bioeden.com Cheshire, UK intelliHep Drug discovery www.intellihep.com Liverpool, UK Diagenic AsA In vitro diagnostics www.diagenic.com Oslo, Norway Medeia therapeutics, ltd. Drug discovery www.medeiatherapeutics.com Kuopio, Finland
innogenetics nv Biological and diagnostic products www.innogenetics.com Gent, Belgium schwarz pharma Pharmaceuticals www.schwarzpharma.com Monheim, Germany
Astellas pharma, inc. Pharmaceuticals www.astellas.com Tokyo, Japan
JsW life sciences Full service contract research organization www.jswresearch.com Grambach, Austria
Hadasit Medical research services & Development, ltd. Technology transfer company www.hadasit.co.il Jerusalem, Israel biorap technologies Technology transfer company www.bio-rap.com Haifa, Israel trophos sA Pharmaceuticals www.trophos.com Marseille, France siena biotech Drug discovery www.sienabiotech.com Siena, Italy brainstorm cell therapeutics, inc. Stem cell technologies www.brainstorm-cell.com Petach Tikva, Israel prana biotechnology Drug discovery www.pranabio.com Parkville, Australia Qrxpharma limited Specialty pharmaceuticals www.qrxpharma.com Sydney, Australia
Intelligence by Anne Vis All rights reserved. www.sunnysites.org
IN NEUROSCIENCE
editor-in-chief: idan segev
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AbNORMAl MITOChONDRIAl DyNAMICS AND NEURODEGENERATION

108 | May 2010 | Volume 4 | Issue 1

May 2010 | Volume 4 | Issue 1 | 109

CEll TO CEll TRANSMISSION OF SyNUClEINOPAThy: IS IT A KEy MEChANISM?

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May 2010 | Volume 4 | Issue 1 | 111

DEMENTIA WITh lEWy bODIES

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May 2010 | Volume 4 | Issue 1 | 113

PARKINSONS DISEASE: ADVANCES IN MOlECUlAR NEUROPAThOlOGy

114 | May 2010 | Volume 4 | Issue 1

AMyOTROPhIC lATERAl SClEROSIS

May 2010 | Volume 4 | Issue 1 | 115

CURRENT OUTlOOK ON hUNTINGTONS DISEASE

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May 2010 | Volume 4 | Issue 1 | 117

ChOlESTEROl AND AlZhEIMERS DISEASE

118 | May 2010 | Volume 4 | Issue 1

High plasma cholesterol

Increased levels of oxysterols

Blood brain barrier leakage

Increased entrance into the brain of neurotoxins and oxysterols

Impairment of cholesterol distribution and clearance

Accumulation of cholesterol in neurons

Increased APP processing by BACE Increased production of A Decreased clearance of A