Journal of Neurochemistry - 2021 - Kumar - Reactive Astrogliosis A Friend or Foe in The Pathogenesis of Alzheimer S

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Received: 30 October 2021 Revised: 13 December 2021 Accepted: 15 December 2021
DOI: 10.1111/jnc.15565
REVIEW
Reactive astrogliosis: A friend or foe in the pathogenesis of

Alzheimer’s disease
Amit Kumar1 | Igor C. Fontana1 | Agneta Nordberg1,2
1
Division of Clinical Geriatrics, Center
for Alzheimer Research, Department of Abstract
Neurobiology, Care Sciences and Society,
Astrocytes are highly efficient homeostatic glial cells playing a crucial role in opti-
Karolinska Institutet, Stockholm, Sweden
2
Theme Aging, Karolinska University
mal brain functioning and homeostasis. Astrocytes respond to changes in brain ho-
Hospital, Stockholm, Sweden moeostasis following central nervous system (CNS) injury/diseased state by a specific
Correspondence
defence mechanism called reactive astrogliosis. Recent studies have implicated and
Agneta Nordberg, Division of Clinical placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease
Geriatrics, Center for Alzheimer
Research, Department of Neurobiology,
(AD) and other neurodegenerative disorders. The AD biomarker field is evolving rap-
Care Sciences and Society, Karolinska idly with new findings providing strong evidence which supports the notion that a
Institutet, NEO, 7th floor, Stockholm
14157, Sweden.
reactive astrogliosis is an early event in the time course of AD progression which may
Email: Agneta.K.Nordberg@ki.se precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in
Funding information
vitro postmortem brain imaging studies demonstrated ‘a first and second wave’ of re-
Stiftelsen för Strategisk Forskning (SSF), active astrogliosis in AD with distinct close-loop relationships with other pathological
Grant/Award Number: RB13-0192;
Loo och Hans Ostermans Stiftelse för
biomarkers at different stages of the disease. At the end stages, reactive astrocytes
Medicinsk Forskning; Gun och Bertil are found to be associated, or in proximity, with amyloid plaque and tau pathological
Stohnes Stiftelse; Stiftelsen för Gamla
Tjänarinnor; The KI foundation for
deposits in postmortem AD brains. Several new PET-tracers, which are being in pipe-
Geriatric Diseases; The Tore Nilsson line and validated at a very fast pace for mapping and visualising reactive astrogliosis
Foundation; The Swedish Brain
Foundation; The Stockholm County
in the brain, will provide further invaluable mechanistic insights into AD and other
Council -Karolinska Institutet regional non-AD dementia pathologies. The complementary roles of microglia and astrocyte
agreement on medical training and clinical
research (ALF); Swedish Research Council,
activation in AD progression, along with the clinical value of new fluid astrocytes
Grant/Award Number: 2017-02965, 2017- biomarkers in the context of existing biomarkers, are the latest avenue that needs
06086 and 2020-01990; The Swedish
Alzheimer Foundation; The Swedish
further exploration.
Dementia Foundation; The Center for
Innovative Medicine (CIMED)KI Stockholm KEYWORDS
Region astrocytes, biomarkers, BU99008, DED, GFAP, imidazoline 2 binding sites, microglia,
PET-Imaging, PET-ligands, postmortem brain, reactive astrogliosis, SMBT-1
1 | I NTRO D U C TI O N (Jäkel & Dimou, 2017; Ransom & Sontheimer, 1992; Rodríguez et al.,
2016; Sajja et al., 2016). In the 19th century, glial cells were mostly
Glial cells are the key architects of the central nervous system (CNS) regarded by many neuroanatomists of that time as a key element
and are responsible for its development, regulation, and degeneration in the pathology (Verkhratsky et al., 2019). With time, researchers
Abbreviations: DED, deutrium-l-deprenyl; GFAP, glial fibrillary acidic protein; I2BS, imidazoline-2 binding sites; MAO B, monoamine oxidase B.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry
Journal of Neurochemistry. 2023;164:309–324. |

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310 KUMAR et al.
started to learn and explore more about glia cells and were surprised astrogliosis, specifically in the progression of AD, in a broader sense
by their deep connection in one or another way in almost all of the with regards to astrocyte heterogeneity, recently published in vitro
CNS physiological functions. As of now, glial cell populations can be and in vivo studies focused on PET-imaging, plasma, and cerebro-
subdivided into four major categories (1) Astroglia (2) Microglia (3) spinal fluid (CSF) biomarkers. We will also discuss and present a
Oligodendroglia, which include oligodendrocytes and their precur- new perspective on the ongoing debates concerning (1) Astrocytes
+
sors NG2 glia cells, with their percentages varying significantly in or microglia—who is the first responder and (2) GFAP being a true
different regions of the human brain (Jäkel & Dimou, 2017). marker of reactive astrogliosis in AD pathology.
Astrocytes account for approximately 20–4 0% of the glial cell
population in the human CNS and are considered as the key ‘homeo-
static cells’ tiling and supporting the whole brain and the spinal cord 2 | A S TRO C Y TE S PATH O LO G I C A L
for optimal functioning and neuronal information transfer (Fakhoury, C H A N G E S : N O N - R E AC TI V E TO R E AC TI V E
2018; Jäkel & Dimou, 2017; Vasile et al., 2017). The name ‘astrocyte’ S TATE
first emerged in the late 19th century to describe star-shaped glial
cells, and, despite their electrical silence and non-neuronal attributes, As we started to drift away and challenge the neuron-centric con-
researchers argued that they have much broader and vital functions cepts for neuropathological changes, more and more focus is di-
(Verkhratsky & Butt, 2018; Verkhratsky & Nedergaard, 2018). As we rected towards neuroglia to understand their diverse role in the
move forward in time, a plethora of evidence highlighted astrocytes evolution of several neuropsychiatric disorders. It would not be
involvement in a wide array of physiological functions, such as ho- wrong to say at this point, that we begin to appreciate more and
meostasis of neurotransmitters and neuromodulators, extracellular more the multifaceted and rather complex role of astrocytes in these
ions and pH, metabolic support, blood-brain barrier (BBB) integrity, disorders. Astrocytes’ pathological changes can be represented ei-
synaptic plasticity, connectivity and many more. Morphologically, ther by a (1) non-reactive state or (2) reactive state. The non-reactive
astrocytes are very diverse and heterogenous and their molecular state mostly includes transformations, such as astrodegeneration
subtypes can differ significantly depending on their developmen- and pathological remodelling, whereas the reactive state is charac-
tal origin and brain regions. Diversity of astrocytes in CNS is very terised by a distinct phenotypic state/mechanism called reactive as-
broad (Verkhratsky et al., 2019) but classically, they are categorised trocytes/reactive astrogliosis. (Verkhratsky et al., 2017).
into white matter fibrous and grey matter protoplasmic astrocytes Astrodegeneration leading to morphological atrophy and loss
(Perez-Nievas & Serrano-Pozo, 2018). Gray matter protoplasmic as- of function is prominent in several neurological and psychiatric
trocytes represent the cortical and sub-cortical population of astro- disorders, such as schizophrenia and major depressive disorder. In
cytes and have been the key target of research so far. They have a amyotrophic lateral sclerosis (ALS), astrocytes atrophy followed
typical ‘bush-like’ morphology with fine thread-like projections clas- by increased cell death can interfere with glutamate uptake caus-
sified as leaflets (Figure 1a) extending till pre-and post-synaptic ter- ing silencing and degeneration of motor neuronal activity (Rossi
minals for regulatory support (Perez-Nievas & Serrano-Pozo, 2018). et al., 2008), whereas in AD, it has been linked with early synap-
Most importantly, astrocytes form a second arm (parenchymal) of tic loss and cognitive impairment (Verkhratsky et al., 2010, 2015).
defence in the brain following the BBB (which forms the first line of Clasmatodendrosis, which is a form of astrodegeneration character-
defence against invading pathogens, harmful chemical agents/mol- ised by extreme terminal disintegration, fragmentation, or beading
ecules, and harmful immune cells/mediators (Muldoon et al., 2013)) of the distal cell processes, has been also observed in postmortem
by responding to neuroinflammation/injuries through an activation neuropathological specimen of seizures, cerebral ischaemia as well
process/state called reactive astrogliosis (Figure 1c) (Escartin et al., as in elderly/ageing brain (Balaban et al., 2021). At the same time,
2021). They become hypertrophic and show over-expression/high the pathological remodelling of astrocytes results in the possession
immunoreactivity of the astrocyte marker protein called glia fibril- of toxic characteristics/functions which promote the pathophysiol-
lary acidic protein (GFAP), a cytoskeleton intermediate filaments ogy of the disease. For example, in mesial temporal lobe epilepsy,
protein (Carter, Herholz, et al., 2019; Liddelow & Barres, 2017; Pekny abnormal astrocyte morphological changes and uncoupling in the
& Pekna, 2016; Pekny et al., 2016). Over the past few decades, sev- hippocampus disrupted the K(+) homeostasis and progression of
eral studies have suggested a broad role of reactive astrogliosis in spontaneous seizures (Bedner et al., 2015). This study led to the
the pathogenesis of Alzheimer's disease (AD) and other neurogene- point that mesial temporal lobe epilepsy could have a more glia-
rative disorders (Carter, Herholz, et al., 2019; Gonzalez-Reyes et al., based origin instead of a neuronal one, challenging the established
2017; Liddelow & Barres, 2017; Matias et al., 2019; Pekny & Pekna, notion of epilepsy being a neuronal syndrome. Another example
2016; Pekny et al., 2016; Siracusa et al., 2019; Verkhratsky et al., includes Alexander disease, where gain of new toxic functions by
2010). Findings even showed that reactive astrogliosis could pre- astrocytes and GFAP mutations drove the pathology (Messing et al.,
cede early pathological hallmarks of AD, such as amyloid-β (Aβ) and 2012).
Tau during disease progression (Figure 2) (Carter et al., 2012, 2019; Reactive astrogliosis, as mentioned above, is the acquisition of
Marutle et al., 2013; Rodriguez-Vieitez et al., 2015, 2016; Schöll ‘reactive phenotype/state’ by astrocytes in response to a CNS in-
et al., 2015). In this review, we want to explore the role of reactive jury (Escartin et al., 2021). From the evolutionary point of view, it
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F I G U R E 1 Astrocyte and microglia activation in AD. (a) Astrocytes in the brain of postmortem AD patient as demonstrated by GFAP
immunostaining (brown). The figure is adapted with permission from (Yu et al., 2005). (b) Astrocytes in close proximity of neuritic plaques as
observed with Aβ (brown) and GFAP (light blue) immunostaining in the temporal cortex of AD patient with Swedish mutation and in sporadic
AD patient (insert). The figure is adapted with permission from (Nordberg, 2004). (c) Illustrations showing activation of astrocyte and
microglia in response to CNS injury and Aβ pathology and their further role in the etiology and progression of AD. The current PET-imaging
tracers and fluid biomarkers (blood and CSF) for assessing and monitoring reactive astrogliosis and microglia activation in AD are also
highlighted. CXCL1, chemokine (C-X-C motif) ligand 1; DED, deutrium-l-deprenyl; GFAP, glial fibrillary acidic protein; IL-8, interleukin-8; PET,
positron emission tomography; sTREM2, soluble triggering receptor expressed on myeloid cells 2; TGF-alpha, transforming growth factor
alpha; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand
is a conserved defence mechanism that regulates neuroinflamma- to pathology’ (Escartin et al., 2021). The complexity of reactive as-
tion, limits the site of damage by forming a perilesion barrier and trogliosis and the resulting astrocyte heterogeneity is very puzzling
compact glial scar with fibromeningeal and other glia cells (i.e. aniso- and can change from disease to disease. These transformations
morphic astrogliosis) and promotes post-injury neuronal function re- could range from beneficial to malfunctional/toxic states depend-
covery (via isomorphic astrogliosis) (Fakhoury, 2018; Guttenplan & ing on the disease and the pathways inducing them. For example, in
Liddelow, 2019; Sofroniew & Vinters, 2010; Verkhratsky et al., 2010, traumatic brain injury (Levine et al., 2016) and motor neuron injury
2013). There are many names and definitions in the field for reac- (Tyzack et al., 2014), activation of the transcription factor STAT3
tive astrogliosis, but according to the recently published consensus (signal transducer and activator of transcription 3) promoted astro-
statement by a group of experts, in order to put forward uniform cyte (or astroglial) resilience (which is defined by set of successful
guidelines for the reactive astrocyte nomenclature and definitions, astroprotective responses that maintain cell-intrinsic homeostatic
‘reactive astrogliosis is a process whereby, astrocytes engage in mo- functions in neural circuits while promoting both neuronal and as-
lecularly defined programmes involving changes in transcriptional trocyte survival (Escartin et al., 2021)), which prevented necrosis and
regulation, as well as biochemical, morphological, metabolic, and supported neuronal integrity, whereas in AD mouse models, it was
physiological remodelling, which ultimately result in gain of new the inhibition of STAT3 that ameliorated the pathology (Reichenbach
function(s) or loss or up-regulation of homeostatic ones, in response et al., 2019). AD is one of the key brain disorders where research on
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F I G U R E 2 The ‘first (early)’ and ‘second (late)’ wave of reactive astrogliosis in AD pathology. (a) In vivo brain retention of 11C-PiB, 11C-DED
and 18F-FDG in pre-symptomatic mutation carriers (pMC) autosomal dominant AD (ADAD) case at baseline and follow-up (after ~3 years).
The red and yellow scales correspond to contrasts showing higher retention, and the blue scales correspond to lower retention.
Adapted with permission from (Rodriguez-Vieitez et al., 2016). (b) In vivo 11C-DED micro-PET studies in amyloid precursor protein
Swedish mutation (APPswe) and wild-t ype mice models showing differential time course for reactive astorgliosis in APPswe mice as
compared to WT mice. 11C-DED binding was higher at 6-months of age but begin to decline with age (23-months of age; left panel) whereas
no change in 11C-DED binding was observed in WT mice with age (almost similar binding at 11-and 24-months of age; right panel). All
images are presented in a common scale from 0.0 to 0.4 units of non-displaceable binding potential (BPND). Adapted with permission from
(Rodriguez-Vieitez et al., 2015). (c) In vitro large brain section autoradiography showing increase binding of 3H-BU99008 in sporadic AD case
as compared to control at the end stages. The color scale represent binding from low (green) to high (dark red). Adapted with permission
from (Kumar et al., 2021). (d) The illustration showing hypothetical model of reactive astrogliosis ‘first’ and ‘second’ wave at different stages
of AD in context of other pathological hallmarks. ADAD, autosomal dominant AD case; DED, deutrium-l-deprenyl, FDG, flurodeoxyglucose;
PIB, Pittsburgh Compound B
astrocyte reactivity ‘reactive astrogliosis’ has been the central focus include tau PET and CSF phosphorylated tau whereas neurodegen-
in recent times, with several published and ongoing studies aimed at eration/neuronal injury (N) will be represented by atrophy on MRI,
deciphering its underlying mechanisms and role in the AD pathogen- FDG PET and CSF total-t au. The [AT(N)] criteria were presented to
esis for future diagnostic and therapeutic interventions. unify and create a common language in the research community
to provide more flexibility to researchers for testing different hy-
potheses regarding interactions between biomarker-based patho-
3 | R E AC TI V E A S TRO G LI OS I S I N A D : TH E logical hallmarks and cognitive dysfunction. The framework clearly
R E S I LI ENT FRO NTLI N E S O LD I ER cautions against using these guidelines in general medical practice
and scenarios where biomarkers are not ideal for testing a specific
AD is a progressive neurodegenerative disorder and the most com- hypothesis/research goal. The framework is flexible with the pos-
mon form of dementia leading to acute memory loss and a variety sibility of adding new biomarkers to the existing [AT(N)] criteria and
of other cognitive disabilities affecting millions of people world- beyond as a separate category (X) (Hampel et al., 2021) whenever
wide (Atri, 2019; Selkoe, 2011; Winblad et al., 2016). The classical they are validated and available. Similarly, the international work-
hallmarks of AD pathology include Aβ plaques and neurofibrillary ing group (IWG) diagnostic criteria laid the foundation of the current
tau-t angles (Selkoe, 2011). According to the National Institute of framework, initially proposing the concept of ‘prodromal AD’ in diag-
Aging and Alzheimer's Association (NIA-A A) framework guidelines, nostic criteria (Dubois, 2000; Dubois & Albert, 2004; Dubois et al.,
which were published in 2011 and updated recently, AD should be 2007, 2010, 2014, 2016).
defined as a biological construct and diagnosed by its underlying The category (N) is still evolving with the possibility of including
pathological hallmarks and biomarkers (Jack et al., 2011, 2018). The biomarkers of reactive astrogliosis in the near future, which have
biomarkers for diagnosis in living patients can be categorised into Aβ been emerging at a very fast pace, as reactive astrogliosis is now
deposition (A), pathologic tau (T), and neurodegeneration/neuronal considered one of the key pathological processes in the progression
injury (N) and collectively referred to as [AT(N)]. The [AT(N)] criteria of AD. Despite being neuroprotective in nature, aberrant astrogliosis
combine different imaging and fluid (Cerebrospinal fluid (CSF)) bio- can damage neurons and has been found to be closely associated or
markers depending on the nature of pathological hallmarks which in vicinity with Aβ plaques in the brains of AD patients (Figure 1b)
they each measure. For example, Aβ deposition (A) biomarkers will and animal models mimicking different AD pathologies (Carter et al.,
include cortical amyloid PET or low CSF Aβ42. Pathologic tau (T) will 2012; Chun et al., 2018; Gonzalez-Reyes et al., 2017; Meda et al.,
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KUMAR et al. 313
2001; Siracusa et al., 2019; Verkhratsky et al., 2010). In response disease, strokes, epilepsy, multiple sclerosis, neurotrauma, and CNS
to stress/injury conditions, activated astrocytes can upregulate the tumours (Maragakis & Rothstein, 2006; Pekny & Pekna, 2016; Pekny
production of Aβ and the release of pro-inflammatory mediators et al., 2016). All these outcomes and attributes suggest a strong cor-
such as cytokines (Interleuckin-1β and IL-6) and tumour necrosis relation not only between reactive astrogliosis and AD but also point
factor-alpha (TNF-α) (Sajja et al., 2016), thereby initiating a detri- toward the involvement of reactive astrogliosis in a broad spectrum
mental cascade that leads to neuronal dysfunction. Interestingly, Aβ of life-threatening neurodegenerative and CNS disorders; thus mak-
can also recruit astrocytes at the lesion site via the production of ing astrocytes a very promising target for the development of novel
chemotactic molecules such as monocyte chemoattractant protein- in vivo positron-emission tomography (PET) imaging biomarkers/
1(Smits et al., 2002; Wyss-Coray et al., 2003) and abnormally upreg- probes.
ulate astrocyte-mediated nuclear factor-kappa B (NF-kB). It can also PET-imaging is a powerful in vivo technique that uses selective
complement signalling pathways that can disrupt dendritic morphol- and specific PET-tracers to monitor specific proteins, their location
ogy and the neuron-glia network/connectivity and thereby brain and density as well as metabolic processes in the body (Fowler et al.,
cognitive functions (Lian et al., 2015). Astrocytes can internalise 2005). Thanks to recent advances in the field of in vivo biomark-
pathological tau leading to abnormal tau accumulation and propa- ers, different types of PET-tracers, CSF and plasma biomarkers are
gation during AD pathology (Chiarini et al., 2017; Ikeda et al., 1992; currently being used to track Aβ plaques, tau neurofibrillary tangles
Martini-Stoica et al., 2018; Perez-Nievas & Serrano-Pozo, 2018). The (NFTs), glucose metabolism, and neuroinflammatory processes (mi-
exact underlying mechanism involved in tau transport/propagation croglia and astrocytes activation) in AD and other proteinopathies
through astrocytes is still poorly explored (Narasimhan et al., 2017; (Nordberg, 2011, 2014; Perani et al., 2019; Rodriguez-
Vieitez &
Perea et al., 2019). However, the relationship between astrocytes Nordberg, 2018; Saint-Aubert et al., 2017). The recent approval
and tau is starting to evolve more and more with a new study show- of several new Aβ-PET tracers in 2012 by the Food and Drug
ing that extracellular tau oligomers could trigger neuroinflamma- Administration (FDA), along with rapid progress in the development
tion by targeting and inducing astrocyte senescence in the brains of tau-tracers (Saint-Aubert et al., 2017; Villemagne et al., 2018) and
of AD patients by promoting the release of high mobility group box the FDA approval of first tau PET-tracer flortaucipir or AV-1451 (a
1 (HMGB1), a well-
known senescence-
associated inflammation radioactive diagnostic agent for the clinical PET-imaging of NFTs
marker (Gaikwad et al., 2021). The complexity and involvement of in human brain (Jie et al., 2021)) in 2020, suggest that the field is
reactive astrogliosis are not just limited to key AD pathological hall- moving rapidly. There is clearly a high interest in developing novel
marks. It actually goes way beyond, as demonstrated by a recently astrocyte-PET, CSF and plasma biomarkers (discussed in later sec-
published study where severe reactive astrogliosis promoted ex- tions) to better understand the role, in vivo distribution and time
cessive production of hydrogen peroxide (H2O2) from MAO-B, ag- course of astrocyte activation as well as the health of the glial-
gravating pathological features of AD such as tauopathy, neuronal neuronal network for early clinical diagnosis of AD and other de-
atrophy, cognitive decline and eventually death in a newly devel- mentia disorders.
oped animal model of reactive astrocytes (GiD) (Chun et al., 2020).
Another study showed that reactive astrocytes induce memory
impairment in AD mice models by abnormal production or release 4 | I N V ITRO A N D I N V I VO PE T I M AG I N G
of the inhibitory gliotransmitter GABA. The astrocytic GABA was STUDIES
produced by MAO-B and released through bestrophin1 channels to
act on presynaptic GABA receptors, causing impaired spike prob- Despite great progress in the PET-imaging field, we are still lack-
ability, thereby affecting synaptic plasticity and memory (Jo et al., ing specific PET-tracers for visualising the astrocyte process/acti-
2014). Another important aspect where reactive astrocytes seem vation, and very few PET-tracers targeting astrogliosis have been
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to be involved in promoting/regulating neuroinflammation, synap- studied so far. The most common one is C-deutrium-l-deprenyl
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tic dysfunction, and glutamate dysregulation/excitotoxicity in AD, is ( C-
DED) (Carter et al., 2012; Fowler et al., 2005; Rodriguez-
via dysregulation of Ca2+ signalling leading to hyperactivation and/ Vieitez & Nordberg, 2018) which targets the monoamine oxidase
or over-expression of calcineurin (CN; a Ca2+/calmodulin dependent B (MAO-B is a flavin-containing enzyme, overexpressed in both
protein phosphatase) and CN-dependent nuclear factor of activated astrocytes and serotonergic neurons regulating the concentration
T-cells (NFAT4) (Abdul et al., 2009; Pleiss et al., 2016). Up-regulation of amine neurotransmitters in the brain (Bortolato et al., 2008)).
of CN/NFAT4 pathway in turn modulate the expression of glutamate We pioneered in demonstrating an increased in vivo 11C-DED bind-
transporter GLT-1 causing imbalance/loss of glutamate buffering ca- ing in mild cognitive impairment patients (MCI; amyloid positive)
pacity in AD mouse models (Sompol et al., 2017). Please refer to the as compared to controls, MCI (amyloid negative), and AD patients
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review by Sompol and Norris (Sompol & Norris, 2018) for further (Carter et al., 2012). Our in vitro multi-PET studies, including C-
2+
reading regarding Ca dysregulation and reactive astrocytes. DED (Kadir et al., 2011; Lemoine et al., 2017; Marutle et al., 2013),
Moreover, astrocyte-mediated neuroinflammation has also been highlighted the relationship between astrogliosis, fibrillar Aβ and
associated with several other neurodegenerative and CNS disorders glucose metabolism in AD. In postmortem studies performed on
such as ALS, Parkinson's disease, Huntington's disease, Alexander the first AD subject imaged with 11C-PIB (Pittsburgh Compound B;
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314 KUMAR et al.
a PET-tracer that targets Aβ fibrils) (Klunk et al. 2004), we found no presymptomatic ADAD carriers as mentioned above (Rodriguez-
3 3
significant regional correlation between H-PIB and H-DED bind- Vieitez et al., 2016).
ing in different brain regions, while there was a close positive corre- These above-described studies clearly established the reliability
lation between 3H-PIB binding and GFAP levels (Kadir et al., 2011). of MAO-B as an excellent marker for reactive astrogliosis. However,
The laminar distribution of 3H-DED binding compared with 3H-PIB since the expression of MAO-B is not specific to astrocytes and can
in AD postmortem brain was also different (Marutle et al., 2013). also be observed to a great extent in different neuronal families (Lin
Furthermore, in a large number of autopsy AD and control brains, et al., 1993; Vitalis et al., 2002), this further prompts the need for
a positive correlation between 3H-DED and 3H-florbetaben (a PET- more specific astrocyte PET-imaging biomarkers/tracers.
tracer that targets Aβ fibrils) in the hippocampus, temporal and BU99008 is a recently developed novel astrocyte PET-tracer
parietal cortex was observed (Ni et al., 2021). In follow up postmor- (Tyacke et al., 2012), which targets the mitochondrial imidazoline2
tem autoradiography studies with 3H-THK5117 (a PET-tracer that binding sites (I2Bs) predominantly expressed in the outer mitochon-
targets tau deposits) and 3H-DED, we observed a similar laminar drial membrane of the astrocytes and to a lower extent in neurons
cortical brain pattern for tau deposits and activated astrocytes in (Li, 2017; Tyacke et al., 2018). I2Bs represent a highly heterogenous
AD and autosomal-dominant AD (ADAD) cases with PSEN1DE9 and group of proteins that bind with high affinity to 3H-Idazoxan (Li,
AβPParc mutations (Lemoine et al., 2017, 2020). These studies sug- 2017). I2Bs have been proposed to regulate GFAP expression (Olmos
gested a close-knit link between Aβ, tau and reactive astrogliosis et al., 1994) and have shown to be co-expressed with MAO-B in the
and highlighted that different subtype of reactive astrocytes might human frontal cortex during the process of aging (Ballesteros et al.,
be associated with the pathogenesis of AD. 2000). I2Bs are implicated in several neurological and neurodegener-
In vivo-PET studies in presymptomatic ADAD carriers as well ative disorders including AD. Most importantly, postmortem studies
as in vivo micro-PET studies in amyloid precursor protein Swedish have shown that I2Bs density is increased by 63% in AD (Ruiz et al.,
mutation (APPswe) transgenic mice models have together demon- 1993) and could thereby be an ideal surrogate marker to visualise
strated the important finding that reactive astrogliosis was sig- and monitor astrocyte reactivity in the brain during normal and dis-
nificantly increased during the initial stages of AD progression ease/injured states. Initial studies (preclinical and clinical) in animal
preceding the early Aβ deposition in brain. Thus, in a longitudinal models, primates and in healthy human participants, demonstrated
in vivo multi-PET tracer study performed in members of different good specificity, brain uptake, biodistribution and radiation safety
known ADAD families, a significantly elevated reactive astrogliosis profile for the tracer (Kealey et al., 2013; Parker et al., 2014; Tyacke
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(higher C-DED binding) was observed in presymptomatic ADAD et al., 2012, 2018). Building on these studies, we demonstrated for
carriers compared to non-
carriers. The reactive astrogliosis was the first time that 3H-BU99008 could detect/target reactive astro-
significantly elevated even 15–20 years before the onset of clinical gliosis in AD postmortem brains with good specificity and selectiv-
symptoms followed by a decline with increasing Aβ load and time/ ity (Figure 2c) (Kumar et al., 2021). These findings seem to replicate
disease progression (Figure 2a) (Rodriguez-Vieitez et al., 2016; Schöll in vivo in AD patients as well, as demonstrated by Calsolaro and
et al., 2015). Furthermore, a positive correlation has also been ob- colleagues in a pilot study published shortly after our postmortem
served between 11C-DED binding and cerebral glucose hypometab- study using 11C-BU99008 (Calsolaro et al., 2021). Further, they also
olism (measured with 18F-deoxyglucose (18F-FDG) uptake) as well as observed similar findings as DED in vivo with BU99008, namely that
with cortical microstructure in presymptomatic ADAD cases (Carter, reactive astrogliosis was higher in MCI cases as compared to AD
Chiotis, et al., 2019; Vilaplana et al., 2020). A negative correlation cases (Livingston et al., 2021). Interestingly, frozen large brain sec-
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between C-DED and C-PIB in presymptomatic stages of ADAD tion autoradiography showed differences in the binding behaviour
was seen (Carter, Chiotis, et al., 2019), whereas in postmortem brain of 3H-BU99008 and 3H-DED, pointing towards the possibility that
analyses in advanced sporadic AD cases have been observed with a they might be either targeting a different sub-population or specific
positive correlation between deprenyl (3H-DED) and amyloid (3H- subtypes/ phenotypes of astrocytes (Kumar et al., 2021). Please
florbetaben) (Ni et al., 2021). refer to the review by Escartin and colleagues (Escartin et al., 2021)
In order to investigate the possible time course of reactive as- for further reading regarding reactive astrocytes nomenclature and
troglisosis in APPswe transgenic mice models, transgenic mice and definitions (states vs. phenotypes). Higher binding of 3H-BU99008
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control animals underwent micro-PET studies with C-d eprenyl and 3H-DED was also observed in different AD brain regions specif-
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and C-PIB. The APPswe transgenic mice showed higher C-D ED ically in the hippocampus as compared to control. This observation
binding indicating elevated reactive astrogliosis at 6–8 months age complemented previous (Marutle et al., 2013) and current postmor-
11
which preceded the increased Aβ plaque load (increased C-PIB tem studies (Ni et al., 2021), where higher 3H-DED binding in differ-
binding) measured at 18–24 months age of the animals (Figure 2b) ent AD brain regions (prominent in hippocampus), as compared to
(Rodriguez-V ieitez et al., 2015). Thus, a similar pattern of early in- control, at the end stages along with high GFAP immunoreactivity
creased reactive astrogliosis was observed in the APPswe mice was observed.
as in presymptomatic ADAD carriers (Rodriguez-V ieitez et al., There is a clear trend in astrocyte reactivity at different stages
11
2015, 2016). The C-D ED binding in APPswe transgenic mice of AD based on DED binding dynamic changes and GFAP immuno-
declined with age, and a similar behaviour was also observed in reactivity observed in our presymptomatic to symptomatic cases in
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KUMAR et al. 315
vivo-PET, APPswe transgenic mice models micro-PET (Carter et al., assumptions, based on published studies, need further exploration.
2012; Rodriguez-Vieitez et al., 2015, 2016; Schöll et al., 2015) and Ongoing studies in our group and larger patient studies along with
in vitro end stage AD postmortem studies (Figure 2d) (Kadir et al., the development of new promising PET-tracers (such as SMBT-1
2011; Marutle et al., 2013; Ni et al., 2021; Rodriguez-Vieitez et al., Harada et al., 2020; Villemagne et al., 2020), which is in the pipeline)
2015). We can observe an increased DED binding at preclinical / will shed more light on these observations and help to better under-
prodromal stages (reflected by ‘first wave’ in Figure 2d), lower DED stand astrocyte reactivity and heterogeneity as demonstrated here
binding (at AD dementia) and then, at advanced/end stage of AD by ‘first’ and ‘second’ wave in AD pathogenesis.
dementia (postmortem), increase again in DED/BU99008 binding
(represented by ‘second wave’ in Figure 2d). This most likely high-
lights the complexity of astrocyte heterogeneity and points towards 5 | G FA P : A TRU E M A R K E R O R A S H A M?
different astrocyte states or subtypes/phenotypes (e.g. A1, A2, A
(n) and A(n+1) at different stages of AD progression (Escartin et al., The glial fibrillary acidic protein (GFAP) was first isolated by
2021; Liddelow & Barres, 2017). Lawrence Eng and colleagues in 1971 and characterises the main in-
From the data that we have collected from both in vivo PET as termediate filament in astrocytes (Eng et al., 1971). Abnormal GFAP
well as in vitro postmortem brain tissue studies, we can hypothe- up-regulation can indicate changes in astrocytes cytoskeleton integ-
sise that astrocytes act as the first ‘ frontline soldiers’ who respond rity and is being acknowledged as one of the most trusted markers of
to initial injury by soluble Aβ species (Allaman et al., 2010; Narayan astrocyte reactivity/ reactive astrogliosis (Yang & Wang, 2015). The
et al., 2014; Tong et al., 2017; Wyssenbach et al., 2016) by changing current view of astrocyte reactivity in AD suggests that these cells
to reactive (protective) state to restore homeostasis as shown by can be very heterogeneous, assuming different phenotypes that
the ‘first wave’ in Figure 2d but become atrophic and non-functional seem to be region-specific and vary throughout disease progression
upon continuous assault or disease progression which explains (Escartin et al., 2021). Indeed, GFAP immunoreactivity was initially
the low astrocyte reactivity (highlighted by a decline in the curve demonstrated to have a strong co-localisation with Aβ plaques and
after ‘first wave’) during AD dementia. It is also possible that initial NFTs of tau in postmortem analyses of human brain tissue (Hanzel
astrocyte reactivity could be the result of other early pathological et al., 1999). Further studies led by Serrano-Pozzo, provided a re-
changes such as synaptic dysfunction or vascular changes together conceptualisation on how GFAP-reactive astrocytes associate with
with (or independent of) soluble Aβ pathology. On the other hand, AD pathology (Serrano-Pozo et al., 2011). The authors showed that
it is possible that the ‘second wave’ in Figure 2d might represent a Aβ deposition reached a plateau before the onset of symptoms,
sub-population of resilient astrocytes which were dormant during while reactive astrocytes over-expressing GFAP, positively cor-
the preclinical/prodromal and initial AD dementia stages but were related with disease progression and increased number of NFTs
working in the background to prevent the brain from complete fail- (Serrano-Pozo et al., 2011). A recent systematic review encompass-
ure. They in turn could undergo reactive transformations and re- ing 306 qualitative, semi-quantitative, and quantitative studies of
modelling (leading to scar formation) at the advanced AD dementia immunohistochemical analyses of postmortem human brain tissue,
stages—in order to give a last fight in attempting to rescue existing established increased GFAP immunoreactivity as the most observed
brain functions. The second wave represents several possibilities. marker of reactive astrogliosis in AD (Viejo et al., 2021). However,
One possibility is that it most probably reflects the astrocytes ef- detecting GFAP levels in the brain tissue is only possible after the
forts to limit the Aβ lesion/injury region through glial scar forma- demise of the patient. In this context, more refined methods for de-
tion via remodelling (please refer to Sofroniew, 2009; Sun & Jakobs, tecting GFAP in vivo have been developed.
2012) for further reading). This could also somewhat explain why Currently, plasma and CSF biomarker analyses offer an unprec-
we observed a positive correlation between GFAP positivity/over- edented way for assessing the influence of GFAP in AD progression
expression and 3H-PIB and 3H-florbetaben binding at the end stages in living patients. A meta-analysis by Bellaver et al. summarised the
of the disease. Another possibility is that these astrocytes represent main findings of works that investigated GFAP levels in CSF and
a sub-population of ageing astrocytes in AD brains which become plasma (Bellaver et al., 2021). They showed that among 11 cohorts,
reactive with age and display high GFAP expression as reported by including 239 AD patients and 205 cognitively unimpaired (CU) sub-
several studies (please refer to the review by Palmer and Ousman jects, CSF GFAP was increased in AD compared to CU individuals
(2018) for further reading). In line with these speculations, Habibi (Bellaver et al., 2021). Yet, it is important to keep in mind that CSF
et al. have recently demonstrated the presence of a new population GFAP may lack the desired specificity to detect AD, as it can also
of disease-associated astrocytes with high GFAP-state, which they be altered in normal ageing and other neurodegenerative diseases
termed as DAAs, in an AD mouse model (Habib et al., 2020). DAAs (Michel et al., 2021; Nichols et al., 1993; Si et al., 2004). Supporting
seem to be upregulated during the initial phases of the disease and this view, a very recent study evaluated 504 individuals from the
become more prominent and abundant as the disease progresses Swedish BioFINDER-2 cohort, including individuals which are CU,
and are found to be in close proximity to Aβ. Moreover, they also MCI/prodromal, AD, and non-AD disorders (Pereira et al., 2021) and
observed DAAs in aged WT mice and in ageing postmortem human showed that, even though CSF GFAP can predict cognitive decline,
brains which are aligned with the second described possibility. These non-AD individuals had higher levels of GFAP in the CSF compared
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316 KUMAR et al.
to MCI, AD and CU groups (Pereira et al., 2021). At the same time, proposed the amyloid cascade hypothesis, suggesting that Aβ depo-
plasma GFAP in AD may predict Aβ deposition, as measured by Aβ- sition leads to NFTs formation and cell death (Hardy & Higgins,
PET, and cognitive decline (Cicognola et al., 2021; Pereira et al., 2021). 1992). The concept of Aβ driving the development of AD has been
Very interestingly, plasma GFAP levels were unaltered in individuals constantly debated and the failure of many Aβ-t argeting clinical
diagnosed with non-AD dementias, such as frontotemporal demen- trials jeopardised the amyloid cascade hypothesis (Makin, 2018).
tia and Parkinson's disease (Pereira et al., 2021). Even though high Interestingly, the recent (and controversial) approval of Aducanumab
variability to detect GFAP in the plasma was previously observed (Clinical trial ID: NCT02484547), a monoclonal antibody that acti-
(Bellaver et al., 2021), these new lines of evidence could support the vates microglial cells and reduces the concentration of Aβ plaques
application of plasma GFAP for the detection of AD in its early stages in the brain of AD patients, highlighted a key role of microglia in AD
(Cicognola et al., 2021; Pereira et al., 2021) (Benedet et al., 2021). (Haeberlein et al., 2020; Sevigny et al., 2016).
Keeping in mind the complexity of astrocytic heterogeneity reiter- A study led by Keren-Shaul characterised a specific type of mi-
ated in above sections, it is also important to mention that GFAP- croglia in a mouse model of AD using sub-tissue single-cell RNA-seq
positive cells (these cells could be further differentiated into high that undergo changes in morphology, function, and distribution—
and low GFAP-state as demonstrated by Habib et al. (2020) thereby termed disease-associated microglia (DAM) (Keren-Shaul et al.,
adding another level of complexity) may present a single population 2017). Among the microglial genes differentially expressed in DAM,
of reactive astrocytes, which seems to be highly dependent on the the triggering receptor expressed on myeloid cells 2 (TREM2) and
brain region. For instance, in these studies, careful analysis of rodent Tyrobp, which are closely related to Aβ clearance, are upregulated
brains indicates that ~80% of astrocytes in the hippocampus are (Keren-Shaul et al., 2017). The TREM2 is selectively expressed in
GFAP-positive, meanwhile, at least 40% of cells which are S100B- microglial cells and TREM2 knock out in AD mice models seems to
immunoreactive are GFAP-negative (Bushong et al., 2002; Ogata & induce tau seeding and spreading around Aβ plaques (Gratuze et al.,
Kosaka, 2002), but further studies are still needed. Therefore, GFAP 2021). These insights from animal models of AD suggest that TREM2
levels may not provide a full overview of reactive astrogliosis in the is essential for microglial phagocytic function against Aβ plaques and
mammalian brain. However, following in the footsteps of published to prevent tau pathology (Leyns et al., 2019). Indeed, Suarez-C alvet
and ongoing studies in CSF and plasma, we can all agree that GFAP et al. (2019) evaluated 1027 participants of the ADNI study and ob-
can provide initial overview of reactive astrogliosis in the brain and served decreased levels of CSF soluble TREM2 (sTREM2) levels in
combining with other existing (discussed below) and new emerging Aβ+ and T-(N)-cases (Suarez-C alvet et al., 2019). On the other hand,
markers, it may provide a more precise diagnosis of AD pathology in increased CSF P-t au181P and CSF T-t au (indexes of T+ and (N)+, re-
the future (in context of astrocyte reactivity). spectively) correlate with higher levels of sTREM2 (Suarez-C alvet
et al., 2019). A very thorough analysis of the Dominantly Inherited
Alzheimer Network (DIAN) cohort corroborates these findings, indi-
6 | A S TRO C Y TE S O R M I C RO G LI A : W H O I S cating that longitudinal increase in CSF sTREM2 is associated with
FI R S T ? slower deposition of Aβ (Christian et al., 2021). Whether plasma
sTREM2 levels are expressed differently in AD patients must be fur-
Glial cells have crucial roles in protecting the CNS. Historically, as- ther explored, and the influence of different sTREM2 variants (e.g.,
trocytes and microglial cells have been suggested as the main or- the R47H TREM2 variant) should be considered (Ashton et al., 2019;
chestrators of the neuroinflammatory symphony that seems to Park et al., 2021; Vilalta et al., 2021). In fact, it seems that microglial
prevent the brain from evolving into a disordered state. Recent activation could display a biphasic profile, in which different pheno-
studies focused on understanding the early stages of AD suggest types (either beneficial or detrimental) might distinctly respond to
that astrocytes and microglia may contribute to disease progression, the core pathology of AD, a behaviour very similar to astrocytes. In
leading the brain into a perpetual inflammatory state (Greenhalgh this context, Ising and colleagues showed that fibrillar forms of Aβ
et al., 2020). Noteworthy, the different states/phenotypes reactive directly affect microglia following NLRP3 inflammasome activation
astrocytes (as described above in detail) and activated microglia cells which, in turn, induces tau pathology in an animal model of tauop-
assume could differentially impact AD development (illustration in athy, characterising a detrimental profile of microglia activation (il-
Figure 1c) (Escartin et al., 2021; Kumar et al., 2021; Nguyen et al., lustrated in Figure 1c) (Ising et al., 2019). Intriguingly, our in vitro
2020; Ransohoff, 2016). autoradiography also demonstrated that microglial activation (mea-
The microglial cells are resident immune cells in the CNS and sured by [3H]PK11195 binding) was closely related in older animals
constitute 5–10% of total brain cells (Aguzzi et al., 2013). A simplistic with high Aβ deposition (Ni et al., 2014). In accordance with these
view of microglia proposes the existence of pro-inflammatory (M1) findings, a study by Pascoal et al. (2021) evaluated 130 individuals
or anti-inflammatory (M2) phenotype (Mills et al., 2000), a categori- and, using PET-tracers that are selective for microglial activation
sation that has been constantly challenged (Nguyen et al., 2020; ([11C]PBR28), Aβ ([18F]AZD4694), and tau ([18F]MK-6240), demon-
Ransohoff, 2016). In fact, it seems that microglial cells may assume strated that microglial activation may trigger tau spreading—a phe-
a wide range of phenotypes in response to toxins or pathological nomenon that is potentiated by Aβ (illustrated in Figure 1c) (Pascoal
insults in the CNS (Liddelow et al., 2017). In 1992, Hardy & Higgins et al., 2021).
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KUMAR et al. 317
In keeping with these findings, defining whether microglia serve the formation of Aβ plaques, AβOs and Aβ protofibrils may interact
as a friend (for instance inducing Aβ clearance) or foe (such as driving with transporters/receptors in the membrane of astrocytes, such as
tau pathology) should be further evaluated. Based on the results dis- the α7 nicotinic acetyl choline receptor (α7nAChR) (Xiu et al., 2005)
cussed above, one could suggest that neuroinflammatory changes and GLT-1 (Tong et al., 2017). Combined, AβOs and Aβ protofibrils
related to microglia may depend on Aβ deposition in AD (Joshi et al., can be internalised in astrocytes and following a high intracellular
2014; Jung et al., 2015; Serrano-Pozo et al., 2011). On the opposite, accumulation, macrovesicles release Aβ aggregates into the extra-
reactive astrogliosis seems to be a key component in the early stages cellular space, favouring the formation of Aβ plaques (Nagele et al.,
of AD as demonstrated by the ‘first wave’ in the previous section, 2003; Sollvander et al., 2016). Thus, differentially from microglial
prior to the formation of Aβ plaques (Calsolaro et al., 2021; Carter, activation, which could be a consequence of Aβ deposition, reactive
Herholz, et al., 2019; Kumar et al., 2021; Rodriguez-Vieitez et al., astrogliosis via different mechanisms may favour amyloidosis in AD
2015). (Figure 1c). We think the debate regarding who comes first should be
Among the potential markers of reactive astrogliosis (disregard- investigated with a new perspective directed more towards how mi-
ing GFAP, which has been broadly discussed in the previous section) croglia and astrocytes complement each other (via protective or det-
CSF YKL-4 0 and blood S100B are increased in AD patients (Bellaver rimental signalling pathways) in the pathogenesis of AD in response
et al., 2021). The YKL-4 0 is a glycoprotein, primarily expressed in to internal and external triggers.
astrocytes, that seems to be altered in inflammatory-related dis-
eases, such as multiple sclerosis (Malmestrom et al., 2014) and AD
(Llorens et al., 2017). Interestingly, changes in CSF levels of YKL-4 0 7 | CO N C LU D I N G R E M A R K S
are also proposed as an early event in AD. Indeed, YKL-4 0 levels are
increased in MCI patients compared to healthy controls. In addition, The AD biomarkers field is moving at a very fast pace with several
the ratio between CSF YKL-4 0 and Aβ42 is a predictor of cognitive new PET-tracers and fluid biomarkers being in the pipeline and con-
impairment in normal subjects (Craig-Schapiro et al., 2010). Further tinuously validated. These advances have surely shed much needed
experimental evidence has been recently provided to interpret the light on the role of astrocytes and reactive astrogliosis in the patho-
involvement of YKL-4 0 in AD (Lananna et al., 2020). It was shown genesis of AD and improved our understanding of their behaviour
that deletion of the YKL-4 0 promoter gene in APP/PS1 mouse, re- during different stages of disease progression. The in vivo PET-and
duced the formation of insoluble Aβ aggregates in the mouse hippo- postmortem brain tissue studies have provided convincing evidence
campus (Lananna et al., 2020). In a similar fashion, S100B, a calcium that there are two waves of astrocyte reactivity during the whole
sensor protein mostly localised in astrocytes, seems to be highly cycle of AD pathogenesis, i.e the ‘first wave’ during presymptomatic/
expressed in the blood of AD patients in the early stages (Peskind prodromal stage and the ‘second wave’ at the advanced stages of AD
et al., 2001). The over-expression of human S100B in APP/PS1 mice dementia. At this point, we do not know if the ‘two waves’ are unique
led to an increased burden of Aβ (Mori et al., 2010). Moreover, higher for AD but we can speculate that it is based on our studies.
levels of β-secretase were also highlighted in these animals, suggest- If we talk about GFAP as a trusted marker for reactive astro-
ing that S100B may accelerate Aβ release from APP, favouring the gliosis, increasing evidence has shown that GFAP could provide
amyloidogenic pathway in AD (Mori et al., 2010). Thus, it is likely the initial footprint of astrocyte reactivity in the brain. However,
that reactive astrogliosis , as indexed by fluid levels of S100B and GFAP alone is not enough, and we need a combinatorial approach
YLK-4 0, may impact AD pathology, favouring the formation and involving other biomarkers to properly understand the complexity
deposition of Aβ peptide. In addition to fluid biomarkers, reactive and heterogeneity of astrocytes around AD pathology. It is safe to
astrogliosis in AD can also be evaluated with PET-imaging using spe- say that there is still a big divide when it comes to microglia or as-
cific PET-tracers as presented in detail in above section. Combining trocyte in the pathology of AD. The studies have pointed towards
experimental findings and clinical evidence from both fluid and im- a more synergistic behaviour between microglia and astrocytes in
aging biomarker studies discussed above, the concept of high heter- AD. In this regard, the future approaches focused on understand-
ogenicity of reactive astrocytes reactivity in AD is again reinforced ing the complementary role of microglia activation and astrocyte
(Rodriguez-Arellano et al., 2016). reactivity in AD progression will provide valuable insights that will
Whereas additional in vivo PET imaging studies are warranted assist in developing future therapeutic targets and interventions and
to support the role of reactive astrocytes in early AD, cellular mod- benefit in better understanding the disease mechanisms of several
els of AD could help to explore astrocyte-related mechanisms of other neurological disorders. To answer the big question of whether
toxicity in the pre-amyloid phase (Fontana et al., 2020). Soluble Aβ reactive astrogliosis is a friend or foe in AD, we think, based on the
oligomers (AβOs) have been widely demonstrated to affect astro- published studies and evidence, that reactive astrocytes are very
cyte morphology and function in vitro (Allaman et al., 2010; Narayan resilient ‘friendly’ soldiers, that perform whatever functions/tasks
et al., 2014; Tong et al., 2017; Wyssenbach et al., 2016). A potential are needed to maintain the brain homeostasis in normal and disease
mechanism that could pinpoint reactive astrogliosis as a trigger for state till the end. However, under severe stress conditions they be-
amyloidosis in AD involves the internalisation of Aβ peptides in as- come non-functional and even harmful. If we look from a broader
trocytes (illustrated in Figure 1c). Specifically, it seems that prior to perspective, it seems like reactive astrogliosis is keeping the fight
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318 KUMAR et al.
Balaban, D., Miyawaki, E. K., Bhattacharyya, S., & Torre, M. (2021). The
going till the end by undergoing transformations and remodelling to phenomenon of clasmatodendrosis. Heliyon, 7, e07605. https://doi.
limit brain injury and promote cell survival. Nevertheless, these con- org/10.1016/j.heliyon.2021.e07605
clusions will require further investigation and exploration. Ballesteros, J., Maeztu, A. I., Callado, L. F., Gutiérrez, M., García-Sevilla,
J. A., & Meana, J. J. (2000). I2-Imidazoline receptors and mono-
amine oxidase B enzyme sites in human brain: Covariation with
AC K N OW L E D G E M E N T S
age. Neuroscience Letters, 288, 135–138. https://doi.org/10.1016/
This study was financially supported by the Swedish Foundation for S0304-3940(00)01218-0
Strategic Research (SSF) (RB13-0192), the Swedish Research Council Bedner, P., Dupper, A., Hüttmann, K., Müller, J., Herde, M. K., Dublin, P.,
(2017-02965, 2017-06086), the Stockholm County Council-Karolinska Deshpande, T., Schramm, J., Häussler, U., Haas, C. A., Henneberger,
C., Theis, M., & Steinhäuser, C. (2015). Astrocyte uncoupling as a
Institutet regional agreement on medical training and clinical research
cause of human temporal lobe epilepsy. Brain, 138, 1208–1222.
(ALF grant), the Swedish Brain Foundation, the Swedish Alzheimer https://doi.org/10.1093/brain/awv067
Foundation, Foundation for Old Servants, Gun and Bertil Stohne’s Bellaver, B., Ferrari-Souza, J. P., Uglione da Ros, L., Carter, S. F., Rodriguez-
Foundation, Loo and Hans Osterman’s Foundation, the Tore Nilsson Vieitez, E., Nordberg, A., Pellerin, L., Rosa-Neto, P., Leffa, D. T.,
& Zimmer, E. R. (2021). Astrocyte biomarkers in Alzheimer dis-
Foundation, the KI Foundation for Geriatric Diseases, the Swedish de-
ease: A systematic review and meta-analysis. Neurology, 96(24),
mentia foundation, and the Center for Innovative Medicine (CIMED) e2944–e2955. https://doi.org/10.1212/WNL.000000 0000012109
Karolinska Institutet. We would like to thank Prof. Alexei Verkhratsky, Benedet, A. L., Milà-Alomà, M., Vrillon, A., Ashton, N. J., Pascoal, T. A.,
The University of Manchester, for all his valuable comments and in- Lussier, F., Karikari, T. K., Hourregue, C., Cognat, E., Dumurgier,
J., Stevenson, J., Rahmouni, N., Pallen, V., Poltronetti, N. M.,
puts during the preparation of the revised version of the manuscript.
Salvadó, G., Shekari, M., Operto, G., Gispert, J. D., Minguillon, C.,
… Stevensson, A. (2021). Differences between plasma and cerebro-
C O N FL I C T O F I N T E R E S T S spinal fluid glial fibrillary acidic protein levels across the Alzheimer
The authors declare no conflict of interests. disease continuum. JAMA Neurology, 78(12), 1471. https://doi.
org/10.1001/jamaneurol.2021.3671
Bortolato, M., Chen, K., & Shih, J. C. (2008). Monoamine oxidase in-
AU T H O R C O N T R I B U T I O N activation: From pathophysiology to therapeutics. Advanced
AK and AN conceptualised the review. AK, IF and AN wrote the first Drug Delivery Reviews, 60, 1527–1533. https://doi.org/10.1016/j.
draft of the manuscript. All authors approved the final version of the addr.2008.06.002
Bushong, E. A., Martone, M. E., Jones, Y. Z., & Ellisman, M. H. (2002).
manuscript.
Protoplasmic astrocytes in CA1 stratum radiatum occupy separate
anatomical domains. Journal of Neuroscience, 22, 183–192. https://
DATA AVA I L A B I L I T Y S TAT E M E N T doi.org/10.1523/JNEUROSCI.22-01-0 0183.2002
Data sharing is not applicable since no new data were generated for Calsolaro, V., Matthews, P. M., Donat, C. K., Livingston, N. R., Femminella,
this Review article. G. D., Guedes, S. S., Myers, J., Fan, Z., Tyacke, R. J., Venkataraman,
A. V., Perneczky, R., Gunn, R., Rabiner, E. A., Gentleman, S., Parker,
C. A., Murphy, P. S., Wren, P. B., Hinz, R., Sastre, M., … Edison, P.
ORCID (2021). Astrocyte reactivity with late-onset cognitive impairment
Agneta Nordberg https://orcid.org/0000-0001-7345-5151 assessed in vivo using (11)C-BU99008 PET and its relationship with
amyloid load. Molecular Psychiatry. https://doi.org/10.1038/s4138
0-021-01193-z
REFERENCES
Carter, S. F., Chiotis, K., Nordberg, A., & Rodriguez-V ieitez, E. (2019).
Abdul, H. M., Sama, M. A., Furman, J. L., Mathis, D. M., Beckett, T. L., Longitudinal association between astrocyte function and glucose
Weidner, A. M., Patel, E. S., Baig, I., Murphy, M. P., LeVine, H., Kraner, metabolism in autosomal dominant Alzheimer's disease. European
S. D., & Norris, C. M. (2009). Cognitive decline in Alzheimer's dis- Journal of Nuclear Medicine and Molecular Imaging, 46, 348–356.
ease is associated with selective changes in calcineurin/NFAT sig- https://doi.org/10.1007/s00259-018-4217-7
naling. The Journal of Neuroscience: The Official Journal of the Society Carter, S. F., Herholz, K., Rosa-Neto, P., Pellerin, L., Nordberg, A., &
for Neuroscience, 29, 12957–12969. https://doi.org/10.1523/ Zimmer, E. R. (2019). Astrocyte biomarkers in Alzheimer’s disease.
JNEUROSCI.1064-09.2009 Trends in Molecular Medicine, 25, 77–95. https://doi.org/10.1016/j.
Aguzzi, A., Barres, B. A., & Bennett, M. L. (2013). Microglia: Scapegoat, molmed.2018.11.006
saboteur, or something else? Science, 339, 156–161. https://doi. Carter, S. F., Schöll, M., Almkvist, O., Wall, A., Engler, H., Långström, B.,
org/10.1126/science.1227901 & Nordberg, A. (2012 Jan). Evidence for astrocytosis in prodromal
Allaman, I., Gavillet, M., Belanger, M., Laroche, T., Viertl, D., Lashuel, H. Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multi-
A., & Magistretti, P. J. (2010). Amyloid-beta aggregates cause al- tracer PET paradigm combining 11C-Pittsburgh compound B and
terations of astrocytic metabolic phenotype: Impact on neuronal 18F-FDG. Journal of Nuclear Medicine, 53(1), 37–46. https://doi.
viability. Journal of Neuroscience, 30, 3326–3338. org/10.2967/jnumed.110.087031
Ashton, N. J., Suárez-C alvet, M., Heslegrave, A., Hye, A., Razquin, C., Chiarini, A., Armato, U., Gardenal, E., Gui, L., & Dal Prà, I. (2017).
Pastor, P., Sanchez-Valle, R., Molinuevo, J. L., Visser, P. J., Blennow, Amyloid β-e xposed human astrocytes overproduce phospho-
K., Hodges, A. K., & Zetterberg, H. (2019). Plasma levels of soluble tau and overrelease it within exosomes, effects suppressed by
TREM2 and neurofilament light chain in TREM2 rare variant carri- Calcilytic NPS 2143-f urther implications for Alzheimer's ther-
ers. Alzheimer's Research & Therapy, 11, 94. https://doi.org/10.1186/ apy. Frontiers in Neuroscience, 11, 217. https://doi.org/10.3389/
s13195-019-0545-5 fnins.2017.00217
Atri, A. (2019). The Alzheimer's disease clinical spectrum: Diagnosis and Christian, H., Estrella, M.-R ., Yan, L., Brigitte, N., Nicolai, F., Chengjie, X.,
management. The Medical Clinics of North America, 103, 263–293. Marc, S.-C ., Anne, F., Stephanie, S., Brian, G., Tammie, B., Jason, H.,
https://doi.org/10.1016/j.mcna.2018.10.009 Eric, M., Regina, F., Celeste, K., Kai, S., John, M., Gernot, K., Bengt,
|
KUMAR et al. 319
N, … Randall, B. (2021). Longitudinal increase of CSF soluble TREM2 Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C.,
is driven by early aggregation of Aβ42 and associates with slower Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G.,
amyloid deposition and clinical decline in autosomal- dominant Agarwal, A., Allen, N. J., Araque, A., Barbeito, L., Barzilai, A., Bergles,
Alzheimer’s disease. Research Square. https://doi.org/10.21203/ D. E., Bonvento, G., Butt, A. M., Chen, W.-T., Cohen-Salmon, M.,
rs.3.rs-744827/v1 … Verkhratsky, A. (2021). Reactive astrocyte nomenclature, defi-
Chun, H., Im, H., Kang, Y. J., Kim, Y., Shin, J. H., Won, W., Lim, J., Ju, Y., nitions, and future directions. Nature Neuroscience, 24, 312–325.
Park, Y. M., Kim, S., Lee, S. E., Lee, J., Woo, J., Hwang, Y., Cho, H., https://doi.org/10.1038/s41593-020-0 0783- 4
Jo, S., Park, J.-H., Kim, D., Kim, D. Y., … Lee, C. J. (2020). Severe re- Fakhoury, M. (2018). Microglia and astrocytes in Alzheimer's disease:
active astrocytes precipitate pathological hallmarks of Alzheimer's Implications for therapy. Current Neuropharmacology, 16, 508–518.
disease via H(2)O(2)(-) production. Nature Neuroscience, 23, 1555– https://doi.org/10.2174/1570159X15666170720095240
1566. https://doi.org/10.1038/s41593-020-0 0735-y Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O.,
Chun, H., Marriott, I., Lee, C. J., & Cho, H. (2018). Elucidating the interac- Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020). Amyloid-
tive roles of glia in Alzheimer's disease using established and newly beta oligomers in cellular models of Alzheimer's disease. Journal of
developed experimental models. Frontiers in Neurology, 9, 797. Neurochemistry, 155(4), 348–369. https://doi.org/10.1111/jnc.15030
https://doi.org/10.3389/fneur.2018.00797 Fowler, J. S., Logan, J., Volkow, N. D., & Wang, G.-J. (2005). Translational
Cicognola, C., Janelidze, S., Hertze, J., Zetterberg, H., Blennow, K., neuroimaging: Positron emission tomography studies of mono-
Mattsson-C arlgren, N., & Hansson, O. (2021). Plasma glial fibrillary amine oxidase. Molecular Imaging and Biology, 7, 377–387. https://
acidic protein detects Alzheimer pathology and predicts future doi.org/10.1007/s11307-0 05-0 016-1
conversion to Alzheimer dementia in patients with mild cognitive Gaikwad, S., Puangmalai, N., Bittar, A., Montalbano, M., Garcia, S.,
impairment. Alzheimer's Research & Therapy, 13, 68. https://doi. McAllen, S., Bhatt, N., Sonawane, M., Sengupta, U., & Kayed, R.
org/10.1186/s13195-021-0 0804-9 (2021). Tau oligomer induced HMGB1 release contributes to cel-
Craig-Schapiro, R., Perrin, R. J., Roe, C. M., Xiong, C., Carter, D., Cairns, lular senescence and neuropathology linked to Alzheimer's disease
N. J., Mintun, M. A., Peskind, E. R., Li, G. E., Galasko, D. R., Clark, and frontotemporal dementia. Cell Reports, 36, 109419. https://doi.
C. M., Quinn, J. F., D'Angelo, G., Malone, J. P., Townsend, R. R., org/10.1016/j.celrep.2021.109419
Morris, J. C., Fagan, A. M., & Holtzman, D. M. (2010). YKL-4 0: A Gonzalez-Reyes, R. E., Nava-Mesa, M. O., Vargas-Sanchez, K., Ariza-
novel prognostic fluid biomarker for preclinical Alzheimer's dis- Salamanca, D., & Mora-Munoz, L. (2017). Involvement of astro-
ease. Biological Psychiatry, 68, 903–912. https://doi.org/10.1016/ cytes in Alzheimer's disease from a neuroinflammatory and oxida-
j.biopsych.2010.08.025 tive stress perspective. Frontiers in Molecular Neuroscience, 10, 427.
Dubois, B. (2000). 'Prodromal Alzheimer's disease': a more useful concept https://doi.org/10.3389/fnmol.2017.00427
than mild cognitive impairment? Current Opinion in Neurology, 13(4), Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M. R., Serrano,
367–369. https://doi.org/10.1097/00019052-200008 000-0 0001 J. R., Colonna, M., Ulrich, J. D., & Holtzman, D. M. (2021). Activated
Dubois, B., & Albert, M. L. (2004). Amnestic MCI or prodromal microglia mitigate Abeta-associated tau seeding and spreading.
Alzheimer's disease? The Lancet Neurology, 3, 246–248. https://doi. Journal of Experimental Medicine, 218, e20210542. https://doi.
org/10.1016/S1474- 4 422(04)00710- 0 org/10.1084/jem.20210542
Dubois, B., Feldman, H. H., Jacova, C., Cummings, J. L., DeKosky, S. T., Greenhalgh, A. D., David, S., & Bennett, F. C. (2020). Immune cell regulation
Barberger-Gateau, P., Delacourte, A., Frisoni, G., Fox, N. C., Galasko, of glia during CNS injury and disease. Nature Reviews Neuroscience,
D., Gauthier, S., Hampel, H., Jicha, G. A., Meguro, K., O'Brien, J., 21, 139–152. https://doi.org/10.1038/s41583-020-0263-9
Pasquier, F., Robert, P., Rossor, M., Salloway, S., … Scheltens, P. Guttenplan, K. A., & Liddelow, S. A. (2019). Astrocytes and microglia:
(2010). Revising the definition of Alzheimer's disease: A new lex- Models and tools. Journal of Experimental Medicine, 216, 71–83.
icon. The Lancet Neurology, 9, 1118–1127. https://doi.org/10.1016/ https://doi.org/10.1084/jem.20180200
S1474- 4 422(10)70223- 4 Habib, N., McCabe, C., Medina, S., Varshavsky, M., Kitsberg, D., Dvir-
Dubois, B., Feldman, H. H., Jacova, C., DeKosky, S. T., Barberger-Gateau, Szternfeld, R., Green, G., Dionne, D., Nguyen, L., Marshall, J. L.,
P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., Chen, F., Zhang, F., Kaplan, T., Regev, A., & Schwartz, M. (2020).
Meguro, K., O'Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, Disease-associated astrocytes in Alzheimer’s disease and aging.
S., Stern, Y., Visser, P. J., & Scheltens, P. (2007). Research criteria for Nature Neuroscience, 23, 701– 706. https://doi.org/10.1038/
the diagnosis of Alzheimer's disease: Revising the NINCDS-ADRDA s41593-020-0624-8
criteria. The Lancet Neurology, 6, 734–746. https://doi.org/10.1016/ Haeberlein, S. B., von Hehn, C., Tian, Y., Chalkias, S., Muralidharan, K.
S1474- 4 422(07)70178-3 K., Chen, T., Wu, S., Skordos, L. A., Nisenbaum, L., Rajagovindan,
Dubois, B., Feldman, H. H., Jacova, C., Hampel, H., Molinuevo, J. L., R., Dent, G., Harrison, K., Nestorov, I., Zhu, Y., Mallinckrodt, C., &
Blennow, K., DeKosky, S. T., Gauthier, S., Selkoe, D., Bateman, R., Sandrock, A. (2020). Emerge and engage topline results: Phase 3
Cappa, S., Crutch, S., Engelborghs, S., Frisoni, G. B., Fox, N. C., studies of aducanumab in early Alzheimer’s disease. Alzheimer's &
Galasko, D., Habert, M.-O., Jicha, G. A., Nordberg, A., … Cummings, Dementia, 16, e047259. https://doi.org/10.1002/alz.047259
J. L. (2014). Advancing research diagnostic criteria for Alzheimer's Hampel, H., Cummings, J., Blennow, K., Gao, P., Jack, C. R. Jr, & Vergallo,
disease: The IWG-2 criteria. The Lancet Neurology, 13, 614–629. A. (2021). Developing the ATX(N) classification for use across the
https://doi.org/10.1016/S1474- 4 422(14)70090- 0 Alzheimer disease continuum. Nature Reviews. Neurology, 17, 580–
Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, 589. https://doi.org/10.1038/s41582-021-0 0520-w
S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., Broich, K., Hanzel, D. K., Trojanowski, J. Q., Johnston, R. F., & Loring, J. F. (1999).
Cavedo, E., Crutch, S., Dartigues, J.-F., Duyckaerts, C., Epelbaum, High-throughput quantitative histological analysis of Alzheimer's
S., Frisoni, G. B., Gauthier, S., Genthon, R., … Jack, C. R. (2016). disease pathology using a confocal digital microscanner. Nature
Preclinical Alzheimer's disease: Definition, natural history, and Biotechnology, 17, 53–57. https://doi.org/10.1038/5225
diagnostic criteria. Alzheimer's & Dementia: the Journal of the Harada, R., Hayakawa, Y., Ezura, M., Lerdsirisuk, P., Du, Y., Ishikawa, Y.,
Alzheimer's Association, 12, 292– 323. https://doi.org/10.1016/ Iwata, R., Shidahara, M., Ishiki, A., Kikuchi, A., Arai, H., Kudo, Y.,
j.jalz.2016.02.002 Yanai, K., Furumoto, S., & Okamura, N. (2020). (18)F-SMBT-1: A
Eng, L. F., Vanderhaeghen, J. J., Bignami, A., & Gerstl, B. (1971). An acidic selective and reversible positron-emission tomography tracer for
protein isolated from fibrous astrocytes. Brain Research, 28, 351– monoamine oxidase-B imaging. Journal of Nuclear Medicine, 62,
354. https://doi.org/10.1016/0006-8993(71)90668-8 253–258. https://doi.org/10.2967/jnumed.120.244400.
|
320 KUMAR et al.
Hardy, J. A., & Higgins, G. A. (1992). Alzheimer's disease: The amyloid cas- Klunk, W. E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt,
cade hypothesis. Science, 256, 184–185. https://doi.org/10.1126/ D. P., Bergström, M., Savitcheva, I., Huang, G.-F., Estrada, S., Ausén,
science.1566067 B., Debnath, M. L., Barletta, J., Price, J. C., Sandell, J., Lopresti,
Ikeda, K., Haga, C., Akiyama, H., Kase, K., & Iritani, S. (1992). Coexistence B. J., Wall, A., Koivisto, P., Antoni, G., … Långström, B. (2004).
of paired helical filaments and glial filaments in astrocytic pro- Imaging brain amyloid in Alzheimer's disease with Pittsburgh
cesses within ghost tangles. Neuroscience Letters, 148, 126–128. Compound-B. Annals of Neurology, 55, 306–319.
https://doi.org/10.1016/0304-3940(92)90820 -W Kumar, A., Koistinen, N. A., Malarte, M. L., Nennesmo, I., Ingelsson, M.,
Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., Vieira- Ghetti, B., Lemoine, L., & Nordberg, A. (2021). Astroglial tracer
Saecker, A., Schwartz, S., Albasset, S., McManus, R. M., Tejera, D., BU99008 detects multiple binding sites in Alzheimer’s disease brain.
Griep, A., Santarelli, F., Brosseron, F., Opitz, S., Stunden, J., Merten, Molecular Psychiatry, https://doi.org/10.1038/s41380-021-01101-5.
M., Kayed, R., Golenbock, D. T., Blum, D., … Heneka, M. T. (2019). Lananna, B. V., McKee, C. A., King, M. W., Del-A guila, J. L., Dimitry, J. M.,
NLRP3 inflammasome activation drives tau pathology. Nature, 575, Farias, F. H. G., Nadarajah, C. J., Xiong, D. D., Guo, C., Cammack,
669–673. https://doi.org/10.1038/s41586-019-1769-z A. J., Elias, J. A., Zhang, J., Cruchaga, C., & Musiek, E. S. (2020).
Jack, C. R. Jr, Albert, M. S., Knopman, D. S., McKhann, G. M., Sperling, Chi3l1/YKL-4 0 is controlled by the astrocyte circadian clock and
R. A., Carrillo, M. C., Thies, B., & Phelps, C. H. (2011). Introduction to the regulates neuroinflammation and Alzheimer's disease pathogen-
recommendations from the National Institute on Aging-Alzheimer's esis. Science Translational Medicine. 12(574):eaax3519. https://doi.
Association workgroups on diagnostic guidelines for Alzheimer's dis- org/10.1126/scitranslmed.aax3519
ease. Alzheimer's & Dementia: the Journal of the Alzheimer's Association, Lemoine, L., Gillberg, P.-G ., Bogdanovic, N., Nennesmo, I., Saint-Aubert,
7, 257–262. https://doi.org/10.1016/j.jalz.2011.03.004 L., Viitanen, M., Graff, C., Ingelsson, M., & Nordberg, A. (2020).
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Amyloid, tau, and astrocyte pathology in autosomal-dominant
Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, Alzheimer’s disease variants: AβPParc and PSEN1DE9. Molecular
J., Liu, E., Molinuevo, J. L., Montine, T., Phelps, C., Rankin, K. P., Psychiatry, https://doi.org/10.1038/s41380 -020-0 817-2.
Rowe, C. C., Scheltens, P., Siemers, E., Snyder, H. M., … Silverberg, Lemoine, L., Saint-Aubert, L., Nennesmo, I., Gillberg, P.-G ., & Nordberg,
N. (2018). NIA-A A research framework: Toward a biological defini- A. (2017). Cortical laminar tau deposits and activated astro-
tion of Alzheimer's disease. Alzheimer's & Dementia: the Journal of cytes in Alzheimer’s disease visualised by 3H-THK5117 and 3H-
the Alzheimer's Association, 14, 535–562. https://doi.org/10.1016/ deprenyl autoradiography. Scientific Reports, 7, 45496. https://doi.
j.jalz.2018.02.018 org/10.1038/srep45496
Jäkel, S., & Dimou, L. (2017). Glial cells and their function in the adult brain: Levine, J., Kwon, E., Paez, P., Yan, W., Czerwieniec, G., Loo, J. A., Sofroniew,
A journey through the history of their ablation. Frontiers in Cellular M. V., & Wanner, I.-B. (2016). Traumatically injured astrocytes re-
Neuroscience, 11, 24. https://doi.org/10.3389/fncel.2017.00024. lease a proteomic signature modulated by STAT3-dependent cell
Jie, C. V. M. L., Treyer, V., Schibli, R., & Mu, L. (2021). Tauvid™: The first survival. Glia, 64, 668–694. https://doi.org/10.1002/glia.22953
FDA-approved PET tracer for imaging tau pathology in Alzheimer's Leyns, C. E. G., Gratuze, M., Narasimhan, S., Jain, N., Koscal, L. J.,
disease. Pharmaceuticals (Basel), 14, 110. https://doi.org/10.3390/ Jiang, H., Manis, M., Colonna, M., Lee, V. M. Y., Ulrich, J. D., &
ph14020110 Holtzman, D. M. (2019). TREM2 function impedes tau seeding in
Jo, S., Yarishkin, O., Hwang, Y. J., Chun, Y. E., Park, M., Woo, D. H., Bae, neuritic plaques. Nature Neuroscience, 22, 1217–1222. https://doi.
J. Y., Kim, T., Lee, J., Chun, H., Park, H. J., Lee, D. Y., Hong, J., Kim, org/10.1038/s41593-019-0 433-0
H. Y., Oh, S.-J., Park, S. J., Lee, H., Yoon, B.-E., Kim, Y. S., … Lee, Li, J. X. (2017). Imidazoline I2 receptors: An update. Pharmacology &
C. J. (2014). GABA from reactive astrocytes impairs memory in Therapeutics, 178, 48–56. https://doi.org/10.1016/j.pharmthera.
mouse models of Alzheimer's disease. Nature Medicine, 20, 886– 2017.03.009
896. https://doi.org/10.1038/nm.3639 Lian, H., Yang, L., Cole, A., Sun, L., Chiang, A. C.-A ., Fowler, S. W., Shim,
Joshi, P., Turola, E., Ruiz, A., Bergami, A., Libera, D. D., Benussi, L., D. J.Rodriguez-Rivera, J., Taglialatela, G., Jankowsk, J. L., Lu, H.-C .,
Giussani, P., Magnani, G., Comi, G., Legname, G., Ghidoni, R., Furlan, & Zheng, H. (2015). NFkappaB-activated astroglial release of com-
R., Matteoli, M., & Verderio, C. (2014). Microglia convert aggre- plement C3 compromises neuronal morphology and function asso-
gated amyloid-beta into neurotoxic forms through the shedding of ciated with Alzheimer's disease. Neuron, 85, 101–115.
microvesicles. Cell Death and Differentiation, 21, 582–593. Liddelow, S. A., & Barres, B. A. (2017). Reactive astrocytes: Production,
Jung, C. K., Keppler, K., Steinbach, S., Blazquez-Llorca, L., & Herms, J. function, and therapeutic potential. Immunity, 46, 957–967. https://
(2015). Fibrillar amyloid plaque formation precedes microglial ac- doi.org/10.1016/j.immuni.2017.06.006
tivation. PLoS One, 10, e0119768. https://doi.org/10.1371/journal. Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen,
pone.0119768 C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S.,
Kadir, A., Marutle, A., Gonzalez, D., Schöll, M., Almkvist, O., Mousavi, M., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker,
Mustafiz, T., Darreh-Shori, T., Nennesmo, I., & Nordberg, A. (2011). N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L.,
Positron emission tomography imaging and clinical progression in Dawson, T. M., … Barres, B. A. (2017). Neurotoxic reactive astro-
relation to molecular pathology in the first Pittsburgh Compound cytes are induced by activated microglia. Nature, 541, 481–487.
B positron emission tomography patient with Alzheimer's disease. https://doi.org/10.1038/nature21029
Brain, 134, 301–317. https://doi.org/10.1093/brain/awq349 Lin, J. S., Kitahama, K., Fort, P., Panula, P., Denney, R. M., & Jouvet, M.
Kealey, S., Turner, E. M., Husbands, S. M., Salinas, C. A., Jakobsen, S., (1993). Histaminergic system in the cat hypothalamus with ref-
Tyacke, R. J., Nutt, D. J., Parker, C. A., & Gee, A. D. (2013). Imaging erence to type B monoamine oxidase. The Journal of Comparative
imidazoline-I2 binding sites in porcine brain using 11C-BU99008. Neurology, 330, 405–420. https://doi.org/10.1002/cne.90330 0309
Journal of Nuclear Medicine, 54, 139–144. Nicholas, R. L., Valeria, C., Rainer, H., Joseph, N., Sanara, R., Steve, G.,
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir- Robin, J. T., Jim, M., Ashwin, V. V., Robert, P., Roger, N. G., Eugenii,
Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-A staiso, D., A. R., Christine, A. P., Philip, S. M., Paul, B. W., David, J. N., Paul,
Toth, B., Itzkovitz, S., Colonna, M., Schwartz, M., & Amit, I. (2017). M. M., & Paul, E. (2021) Relationship between astrocyte reactiv-
A unique microglia type associated with restricting development ity, using novel 11C-BU99008 PET, and glucose metabolism, grey
of Alzheimer's disease. Cell, 169(1276–1290), e1217. https://doi. matter volume and amyloid load in cognitively impaired individuals.
org/10.1016/j.cell.2017.05.018 medRxiv. https://doi.org/10.1101/2021.08.10.21261690
|
KUMAR et al. 321
Llorens, F., Thüne, K., Tahir, W., Kanata, E., Diaz-Lucena, D., Xanthopoulos, Neuroscience, 37, 11406– 11423. https://doi.org/10.1523/JNEUR
K., Kovatsi, E., Pleschka, C., Garcia-Esparcia, P., Schmitz, M., Ozbay, OSCI.1230-17.2017
D., Correia, S., Correia, Â., Milosevic, I., Andréoletti, O., Fernández- Narayan, P., Holmstrom, K. M., Kim, D. H., Whitcomb, D.J., Wilson, M.R.,
Borges, N., Vorberg, I. M., Glatzel, M., Sklaviadis, T., … Zerr, I. (2017). St George-Hyslop, P., Wood, N.W., Dobson, C.M., Cho, K., Abramov,
YKL- 40 in the brain and cerebrospinal fluid of neurodegenera- A.Y., & Klenerman, D. (2014). Rare individual amyloid-beta oligo-
tive dementias. Molecular Neurodegeneration, 12, 83. https://doi. mers act on astrocytes to initiate neuronal damage. Biochemistry,
org/10.1186/s13024-017-0226-4 53, 2442–2453.
Makin, S. (2018). The amyloid hypothesis on trial. Nature, 559, S4–S7. Nguyen, A. T., Wang, K., Hu, G., Wang, X., Miao, Z., Azevedo, J. A., Suh,
https://doi.org/10.1038/d41586-018-05719- 4 E. R., Van Deerlin, V. M., Choi, D., Roeder, K., Li, M., & Lee, E. B.
Malmestrom, C., Axelsson, M., Lycke, J., Zetterberg, H., Blennow, (2020). APOE and TREM2 regulate amyloid-responsive microglia in
K., & Olsson, B. (2014). CSF levels of YKL-4 0 are increased in Alzheimer's disease. Acta Neuropathologica, 140, 477–493. https://
MS and replaces with immunosuppressive treatment. Journal of doi.org/10.1007/s00401-020-02200-3
Neuroimmunology, 269, 87–89. Ni, R., Rodriguez-V ieitez, E., Voytenko, L., Marutle, A., & Nordberg, A.
Maragakis, N. J., & Rothstein, J. D. (2006). Mechanisms of disease: (2014). O4–02-05: Different time course of astrocytosis and am-
Astrocytes in neurodegenerative disease. Nature Clinical Practice yloid deposition in Alzheimer's Appswe Transgenice mice: A multi-
Neurology, 2, 679–689. https://doi.org/10.1038/ncpneuro0355 tracer micropet study. Alzheimer's & Dementia, 10, P253. https://
Martini-Stoica, H., Cole, A. L., Swartzlander, D. B., Chen, F., Wan, doi.org/10.1016/j.jalz.2014.04.394
Y.-W., Bajaj, L., Bader, D. A., Lee, V. M. Y., Trojanowski, J. Q., Liu, Z., Ni, R., Röjdner, J., Voytenko, L., Dyrks, T., Thiele, A., Marutle, A., &
Sardiello, M., & Zheng, H. (2018). TFEB enhances astroglial uptake Nordberg, A. (2021). In vitro characterization of the regional
of extracellular tau species and reduces tau spreading. Journal of binding distribution of amyloid PET tracer Florbetaben and the
Experimental Medicine, 215, 2355–2377. https://doi.org/10.1084/ Glia Tracers Deprenyl and PK11195 in autopsy Alzheimer’s brain
jem.20172158 tissue. Journal of Alzheimer's Disease, 80, 1723–1737. https://doi.
Marutle, A., Gillberg, P.-G ., Bergfors, A., Yu, W., Ni, R., Nennesmo, I., org/10.3233/JAD-201344
Voytenko, L., & Nordberg, A. (2013). 3H-Deprenyl and 3H-PIB au- Nichols, N. R., Day, J. R., Laping, N. J., Johnson, S. A., & Finch, C. E.
toradiography show different laminar distributions of astroglia and (1993). GFAP mRNA increases with age in rat and human brain.
fibrillar β-amyloid in Alzheimer brain. Journal of Neuroinflammation, Neurobiology of Aging, 14, 421–429. https://doi.org/10.1016/0197-
10, 861. https://doi.org/10.1186/1742-2094-10-90 4580(93)90100-P
Matias, I., Morgado, J., & Gomes, F. C. A. (2019). Astrocyte heterogeneity: Nordberg, A. (2004). PET imaging of amyloid in Alzheimer's disease.
Impact to brain aging and disease. Frontiers in Aging Neuroscience, The Lancet Neurology, 3, 519–527. https://doi.org/10.1016/S1474
11, 59. https://doi.org/10.3389/fnagi.2019.00059 -4 422(04)00853-1
Meda, L., Baron, P., & Scarlato, G. (2001). Glial activation in Alzheimer's Nordberg, A. (2011). Molecular imaging in Alzheimer's disease: New per-
disease: The role of Abeta and its associated proteins. Neurobiology spectives on biomarkers for early diagnosis and drug development.
of Aging, 22, 885–893. Alzheimer's Research & Therapy, 3, 34. https://doi.org/10.1186/
Messing, A., Brenner, M., Feany, M. B., Nedergaard, M., & Goldman, J. E. alzrt96
(2012). Alexander disease. The Journal of Neuroscience: The Official Nordberg, A. (2014). Molecular imaging in sporadic Alzheimer's dis-
Journal of the Society for Neuroscience, 32, 5017–5023. https://doi. ease populations and those genetically at risk. Neuro-Degenerative
org/10.1523/JNEUROSCI.5384-11.2012 Diseases, 13, 160–162. https://doi.org/10.1159/000356333
Michel, M., Fiebich, B. L., Kuzior, H., Meixensberger, S., Berger, B., Ogata, K., & Kosaka, T. (2002). Structural and quantitative analysis of
Maier, S., Nickel, K., Runge, K., Denzel, D., Pankratz, B., Schiele, astrocytes in the mouse hippocampus. Neuroscience, 113, 221–233.
M. A., Domschke, K., van Elst, L. T., & Endres, D. (2021). Increased https://doi.org/10.1016/S0306- 4522(02)00041-6
GFAP concentrations in the cerebrospinal fluid of patients with Olmos, G., Alemany, R., Escriba, P. V., & García-Sevilla, J. A. (1994). The ef-
unipolar depression. Translational Psychiatry, 11, 308. https://doi. fects of chronic imidazoline drug treatment on glial fibrillary acidic
org/10.1038/s41398-021-01423-6 protein concentrations in rat brain. British Journal of Pharmacology,
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M. (2000). M-1/M-2 111, 997–1002. https://doi.org/10.1111/j.1476-5381.1994.tb148
macrophages and the Th1/Th2 paradigm. The Journal of Immunology, 42.x
164, 6166–6173. https://doi.org/10.4049/jimmunol.164.12.6166 Palmer, A. L., & Ousman, S. S. (2018). Astrocytes and aging. Frontiers in
Mori, T., Koyama, N., Arendash, G. W., Horikoshi-Sakuraba, Y., Tan, J., Aging Neuroscience, 10, 337. https://doi.org/10.3389/fnagi.2018.
& Town, T. (2010). Overexpression of human S100B exacerbates 00337
cerebral amyloidosis and gliosis in the Tg2576 mouse model of Park, S. H., Lee, E. H., Kim, H. J., Jo, S., Lee, S., Seo, S. W., Park, H. H.,
Alzheimer's disease. Glia, 58, 300–314. Koh, S. H., & Lee, J. H. (2021). The relationship of soluble TREM2 to
Muldoon, L. L., Alvarez, J. I., Begley, D. J., Boado, R. J., del Zoppo, G. other biomarkers of sporadic Alzheimer's disease. Scientific Reports,
J., Doolittle, N. D., Engelhardt, B., Hallenbeck, J. M., Lonser, R. 11, 13050. https://doi.org/10.1038/s41598-021-92101-6
R., Ohlfest, J. R., Prat, A., Scarpa, M., Smeyne, R. J., Drewes, L. Parker, C. A., Nabulsi, N., Holden, D., Lin, S., Cass, T., Labaree, D., Kealey,
R., & Neuwelt, E. A. (2013). Immunologic privilege in the central S., Gee, A. D., Husbands, S. M., Quelch, D., Carson, R. E., Nutt,
nervous system and the blood-brain barrier. Journal of Cerebral D. J., Huang, Y., & Tyacke, R. J. (2014). Evaluation of 11C-BU99008,
Blood Flow and Metabolism, 33, 13– 21. https://doi.org/10.1038/ a PET ligand for the imidazoline2 binding sites in rhesus brain.
jcbfm.2012.153 Journal of Nuclear Medicine, 55, 838–8 44.
Nagele, R. G., D'Andrea, M. R., Lee, H., Venkataraman, V., & Wang, H. Y. Pascoal, T. A., Benedet, A. L., Ashton, N. J., Kang, M. S., Therriault, J.,
(2003). Astrocytes accumulate A beta 42 and give rise to astrocytic Chamoun, M., Savard, M., Lussier, F. Z., Tissot, C., Karikari, T. K.,
amyloid plaques in Alzheimer disease brains. Brain Research, 971, Ottoy, J., Mathotaarachchi, S., Stevenson, J., Massarweh, G., Schöll,
197–209. M., de Leon, M. J., Soucy, J.-P., Edison, P., Blennow, K., … Rosa-
Narasimhan, S., Guo, J. L., Changolkar, L., Stieber, A., McBride, J. D., Silva, Neto, P. (2021). Microglial activation and tau propagate jointly
L. V., He, Z., Zhang, B., Gathagan, R. J., Trojanowski, J. Q., & Lee, V. across Braak stages. Nature Medicine, 27, 1592–1599. https://doi.
M. Y. (2017). Pathological tau strains from human brains recapit- org/10.1038/s41591-021-01456-w
ulate the diversity of Tauopathies in Nontransgenic mouse brain. Pekny, M., & Pekna, M. (2016). Reactive gliosis in the pathogenesis of
The Journal of Neuroscience: The Official Journal of the Society for CNS diseases. Biochimica Et Biophysica Acta (BBA) -Molecular Basis
|
322 KUMAR et al.
of Disease, 1862, 483– 491. https://doi.org/10.1016/j.bbadis. Långström, B., & Nordberg, A. (2016). Diverging longitudinal
2015.11.014 changes in astrocytosis and amyloid PET in autosomal dominant
Pekny, M., Pekna, M., Messing, A., Steinhäuser, C., Lee, J.-M., Parpura, V., Alzheimer's disease. Brain, 139, 922–936. https://doi.org/10.1093/
Hol, E. M., Sofroniew, M. V., & Verkhratsky, A. (2016). Astrocytes: brain/awv404
A central element in neurological diseases. Acta Neuropathologica, Rossi, D., Brambilla, L., Valori, C. F., Roncoroni, C., Crugnola, A., Yokota, T.,
131, 323–345. https://doi.org/10.1007/s00401-015-1513-1 Bredesen, D. E., & Volterra, A. (2008). Focal degeneration of astro-
Perani, D., Iaccarino, L., Lammertsma, A. A., Windhorst, A. D., Edison, cytes in amyotrophic lateral sclerosis. Cell Death and Differentiation,
P., Boellaard, R., Hansson, O., Nordberg, A., & Jacobs, A. H. (2019). 15, 1691–1700. https://doi.org/10.1038/cdd.2008.99
A new perspective for advanced positron emission tomography- Ruiz, J., Martin, I., Callado, L. F., Meana, J. J., Barturen, F., & Garcia-
based molecular imaging in neurodegenerative proteinopathies. Sevilla, J. A. (1993). Non-adrenoceptor [3H]idazoxan binding sites
Alzheimer's & Dementia: the Journal of the Alzheimer's Association, 15, (I2-imidazoline sites) are increased in postmortem brain from pa-
1081–1103. https://doi.org/10.1016/j.jalz.2019.02.004 tients with Alzheimer's disease. Neuroscience Letters, 160, 109–112.
Perea, J. R., López, E., Díez-Ballesteros, J. C., Ávila, J., Hernández, https://doi.org/10.1016/0304-3940(93)90925-B
F., & Bolós, M. (2019). Extracellular monomeric tau is internal- Saint-Aubert, L., Lemoine, L., Chiotis, K., Leuzy, A., Rodriguez-V ieitez, E.,
ized by astrocytes. Frontiers in Neuroscience, 13, 442. https://doi. & Nordberg, A. (2017). Tau PET imaging: Present and future direc-
org/10.3389/fnins.2019.00442 tions. Molecular Neurodegeneration, 12, 19. https://doi.org/10.1186/
Pereira, J. B., Janelidze, S., Smith, R., Mattsson-C arlgren, N., Palmqvist, S., s13024-017-0162-3
Teunissen, C. E., Zetterberg, H., Stomrud, E., Ashton, N. J., Blennow, Sajja, V. S., Hlavac, N., & VandeVord, P. J. (2016). Role of glia in mem-
K., & Hansson, O. (2021 Dec 16). Plasma GFAP is an early marker ory deficits following traumatic brain injury: Biomarkers of glia
of amyloid-β but not tau pathology in Alzheimer's disease. Brain, dysfunction. Frontiers in Integrative Neuroscience, 10, 7. https://doi.
144(11), 3505–3516. https://doi.org/10.1093/brain/awab223 org/10.3389/fnint.2016.00007
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018). Deciphering the astro- Schöll, M., Carter, S. F., Westman, E., Rodriguez-V ieitez, E., Almkvist, O.,
cyte reaction in Alzheimer's disease. Frontiers in Aging Neuroscience, Thordardottir, S., Wall, A., Graff, C., Långström, B., & Nordberg,
10, 114. https://doi.org/10.3389/fnagi.2018.00114 A. (2015). Early astrocytosis in autosomal dominant Alzheimer’s
Peskind, E. R., Griffin, W. S., Akama, K. T., Raskind, M. A., & Van Eldik, disease measured in vivo by multi-tracer positron emission tomog-
L. J. (2001). Cerebrospinal fluid S100B is elevated in the earlier raphy. Scientific Reports, 5, 16404. https://doi.org/10.1038/srep1
stages of Alzheimer's disease. Neurochemistry International, 39, 6404
409–413. https://doi.org/10.1016/S0197- 0186(01)00048-1 Selkoe, D. J. (2011). Alzheimer's disease. Cold Spring Harbor Perspectives
Pleiss, M. M., Sompol, P., Kraner, S. D., Abdul, H. M., Furman, J. L., in Biology, 3, a004457. https://doi.org/10.1101/cshperspect.
Guttmann, R. P., Wilcock, D. M., Nelson, P. T., & Norris, C. M. (2016). a004457
Calcineurin proteolysis in astrocytes: Implications for impaired Serrano-Pozo, A., Mielke, M. L., Gomez-Isla, T., Betensky, R. A., Growdon,
synaptic function. Biochimica Et Biophysica Acta, 1862, 1521–1532. J. H., Frosch, M. P., & Hyman, B. T. (2011). Reactive glia not only
https://doi.org/10.1016/j.bbadis.2016.05.007 associates with plaques but also parallels tangles in Alzheimer's dis-
Ransohoff, R. M. (2016). A polarizing question: Do M1 and M2 microglia ease. American Journal of Pathology, 179, 1373–1384. https://doi.
exist? Nature Neuroscience, 19, 987–991. https://doi.org/10.1038/ org/10.1016/j.ajpath.2011.05.047
nn.4338 Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M.,
Ransom, B. R., & Sontheimer, H. (1992). The neurophysiology of glial Dunstan, R., Salloway, S., Chen, T., Ling, Y., O'Gorman, J., Qian, F.,
cells. Journal of Clinical Neurophysiology, 9, 224–251. https://doi. Arastu, M., Li, M., Chollate, S., Brennan, M.S., Quintero-Monzon,
org/10.1097/00004691-199204 010-0 0005 O., Scannevin, R.H., Arnold, H.M., … Sandrock, A. (2016). The an-
Reichenbach, N., Delekate, A., Plescher, M., Schmitt, F., Krauss, S., Blank, tibody aducanumab reduces Abeta plaques in Alzheimer's disease.
N., Halle, A., & Petzold, G. C. (2019). Inhibition of Stat3-mediated Nature, 537, 50–56.
astrogliosis ameliorates pathology in an Alzheimer's disease model. Si, X., Miguel-Hidalgo, J. J., O'Dwyer, G., Stockmeier, C. A., & Rajkowska,
EMBO Molecular Medicine, 11(2), e9665. https://doi.org/10.15252/ G. (2004). Age-dependent reductions in the level of glial fibril-
emmm.201809665 lary acidic protein in the prefrontal cortex in major depression.
Rodríguez, J. J., Butt, A. M., Gardenal, E., Parpura, V., & Verkhratsky, A. Neuropsychopharmacology, 29, 2088–2096. https://doi.org/10.1038/
(2016). Complex and differential glial responses in Alzheimer's dis- sj.npp.1300525
ease and ageing. Current Alzheimer Research, 13, 343–358. https:// Siracusa, R., Fusco, R., & Cuzzocrea, S. (2019). Astrocytes: Role and
doi.org/10.2174/1567205013666160229112911 functions in brain pathologies. Frontiers in Pharmacology, 10, 1114.
Rodriguez-Arellano, J. J., Parpura, V., Zorec, R., & Verkhratsky, A. https://doi.org/10.3389/fphar.2019.01114
(2016). Astrocytes in physiological aging and Alzheimer's disease. Smits, H. A., Rijsmus, A., van Loon, J. H., Wat, J. W., Verhoef, J., Boven,
Neuroscience, 323, 170–182. https://doi.org/10.1016/j.neuroscien L. A., & Nottet, H. S. (2002). Amyloid-beta-induced chemokine pro-
ce.2015.01.007 duction in primary human macrophages and astrocytes. Journal of
Rodriguez-V ieitez, E., Ni, R., Gulyas, B., Toth, M., Haggkvist, J., Halldin, Neuroimmunology, 127, 160–168.
C., Voytenko, L., Marutle, A., & Nordberg, A. (2015). Astrocytosis Sofroniew, M. V. (2009). Molecular dissection of reactive astrogliosis and
precedes amyloid plaque deposition in Alzheimer APPswe trans- glial scar formation. Trends in Neurosciences, 32, 638–6 47. https://
genic mouse brain: A correlative positron emission tomography doi.org/10.1016/j.tins.2009.08.002
and in vitro imaging study. European Journal of Nuclear Medicine and Sofroniew, M. V., & Vinters, H. V. (2010). Astrocytes: Biology and pa-
Molecular Imaging, 42, 1119–1132. https://doi.org/10.1007/s0025 thology. Acta Neuropathologica, 119, 7–35. https://doi.org/10.1007/
9-015-3 047-0 s00401-0 09-0619-8
Rodriguez-V ieitez, E., & Nordberg, A. (2018). Imaging neuroinflamma- Söllvander, S., Nikitidou, E., Brolin, R., Söderberg, L., Sehlin, D., Lannfelt,
tion: quantification of astrocytosis in a multitracer PET approach. L., & Erlandsson, A. (2016). Accumulation of amyloid-β by astrocytes
Methods in Molecular Biology, 1750, 231–251. result in enlarged endosomes and microvesicle-induced apoptosis
Rodriguez-V ieitez, E., Saint-Aubert, L., Carter, S. F., Almkvist, O., Farid, of neurons. Molecular Neurodegeneration, 11(1), 38. https://doi.
K., Schöll, M., Chiotis, K., Thordardottir, S., Graff, C., Wall, A., org/10.1186/s13024-016-0 098-z
|
KUMAR et al. 323
Sompol, P., Furman, J. L., Pleiss, M. M., Kraner, S. D., Artiushin, I. A., Batten, Verkhratsky, A., Rodrigues, J. J., Pivoriunas, A., Zorec, R., & Semyanov,
S. R., Quintero, J. E., Simmerman, L. A., Beckett, T. L., Lovell, M. A., A. (2019). Astroglial atrophy in Alzheimer’s disease. Pflügers Archiv -
Murphy, M. P., Gerhardt, G. A., & Norris, C. M. (2017). Calcineurin/ European Journal of Physiology, 471, 1247– 1261. https://doi.
NFAT signaling in activated astrocytes drives network hyperexcit- org/10.1007/s00424-019-02310-2
ability in Aβ-bearing mice. The Journal of Neuroscience: The Official Verkhratsky, A., Rodríguez, J. J., & Parpura, V. (2013). Astroglia in neu-
Journal of the Society for Neuroscience, 37, 6132–6148. https://doi. rological diseases. Future Neurology, 8, 149–158. https://doi.
org/10.1523/JNEUROSCI.0877-17.2017 org/10.2217/fnl.12.90
Sompol, P., & Norris, C. M. (2018). Ca(2+), Astrocyte activation and Verkhratsky, A., Zorec, R., & Parpura, V. (2017). Stratification of astro-
Calcineurin/NFAT signaling in age-related neurodegenerative cytes in healthy and diseased brain. Brain Pathology, 27, 629–6 44.
diseases. Frontiers in Aging Neuroscience, 10, 199. https://doi. https://doi.org/10.1111/bpa.12537
org/10.3389/fnagi.2018.00199 Viejo, L., Noori, A., Merrill, E., Das, S., Hyman, B. T., & Serrano-Pozo,
Suarez-C alvet, M., Morenas-Rodriguez, E., Kleinberger, G., Schlepckow, A. (2021). Systematic review of human post-mortem immunohisto-
M. A. A., Caballero, K., Franzmeier, N., Capell, A., Fellerer, K., chemical studies and bioinformatics analyses unveil the complexity
Nuscher, B., Eren, E., Levin, J., Deming, Y., Piccio, L., Karch, C. L., of astrocyte reaction in Alzheimer's disease. Neuropathology and
Cruchaga, C., Shaw, L. M., Trojanowski, J. Q., Weiner, M., Ewers, M., Applied Neurobiology, 1–22. https://doi.org/10.1111/nan.12753
… the Alzheimer’s Disease Neuroimaging Initiative (2019). Early in- Vilalta, A., Zhou, Y., Sevalle, J., Griffin, J. K., Satoh, K., Allendorf, D. H.,
crease of CSF sTREM2 in Alzheimer's disease is associated with tau Suman, D., Puigdellívol, M., Bruzas, A., Burguillos, M. A., Dodd, R.
related-neurodegeneration but not with amyloid-beta pathology. B., Chen, F., Zhang, Y., Flagmeier, P., Needham, L.-M., Enomoto, M.,
Molecular Neurodegeneration, 14, 1. Qamar, S., Henderson, J., Walter, J., … Brown, G. B. (2021). Wild-
Sun, D., & Jakobs, T. C. (2012). Structural remodeling of astrocytes in type sTREM2 blocks Abeta aggregation and neurotoxicity, but the
the injured CNS. The Neuroscientist: A Review Journal Bringing Alzheimer's R47H mutant increases Abeta aggregation. Journal of
Neurobiology, Neurology and Psychiatry, 18, 567–588. https://doi. Biological Chemistry, 296, 100631.
org/10.1177/1073858411423441 Vilaplana, E., Rodriguez-Vieitez, E., Ferreira, D., Montal, V., Almkvist, O.,
Tong, H., Zhang, X., Meng, X., Xu, P., Zou, X., & Qu, S. (2017). Amyloid- Wall, A., Lleó, A., Westman, E., Graff, C., Fortea, J., & Nordberg,
beta peptide decreases expression and function of glutamate A. (2020). Cortical microstructural correlates of astrocyto-
transporters in nervous system cells. International Journal of sis in autosomal-dominant Alzheimer disease. Neurology, 94,
Biochemistry & Cell Biology, 85, 75–8 4. https://doi.org/10.1016/ e2026–e2036. https://doi.org/10.1212/WNL.000000 00000 09405
j.biocel.2017.01.017 Villemagne, V. L., Dore, V., Burnham, S. C., Masters, C. L., & Rowe, C. C.
Tyacke, R. J., Fisher, A., Robinson, E. S., Grundt, P., Turner, E. M., (2018). Imaging tau and amyloid-beta proteinopathies in Alzheimer
Husbands, S. M., Hudson, A. L., Parker, C. A., & Nutt, D. J. (2012). disease and other conditions. Nature Reviews. Neurology, 14,
Evaluation and initial in vitro and ex vivo characterization of the 225–236.
potential positron emission tomography ligand, BU99008 (2-(4,5- Villemagne, V. L., Harada, R., Dore, V., Furumoto, S., Mulligan, R. S., Kudo,
dihydro-1H-imidazol-2-yl)-1- methyl-1H-indole), for the imidazo- Y., Burnham, S. C., Krishnadas, N., Huang, K., Yanai, K., Rowe, C.
line(2) binding site. Synapse (New York, N. Y.), 66, 542–551. https:// C., & Okamura, N. (2020). Evaluation of the novel 18F- labeled
doi.org/10.1002/syn.21541 PET tracer SMBT-1 for imaging astrogliosis in healthy elderly con-
Tyacke, R. J., Myers, J. F. M., Venkataraman, A., Mick, I., Turton, S., trols and A+/T+/(N+) Alzheimer's disease patients. Alzheimer's &
Passchier, J., Husbands, S. M., Rabiner, E. A., Gunn, R. N.Murphy, P. Dementia, 16, e039858.
S., Parker, C. A., & Nutt, D. J. (2018). Evaluation of (11)C-BU99008, Vitalis, T., Fouquet, C., Alvarez, C., Seif, I., Price, D., Gaspar, P., & Cases,
a PET ligand for the Imidazoline2 binding site in human brain. O. (2002). Developmental expression of monoamine oxidases A
Journal of Nuclear Medicine, 59, 1597–1602. and B in the central and peripheral nervous systems of the mouse.
Tyzack, G. E., Sitnikov, S., Barson, D., Adams-C arr, K. L., Lau, N. K., The Journal of Comparative Neurology, 442, 331–3 47. https://doi.
Kwok, J. C., Zhao, C., Franklin, R. J. M., Karadottir, R. T., Fawcett, org/10.1002/cne.10093
J. W., & Lakatos, A. (2014). Astrocyte response to motor neuron Winblad, B., Amouyel, P., Andrieu, S., Ballard, C., Brayne, C., Brodaty,
injury promotes structural synaptic plasticity via STAT3-regulated H., Cedazo-Minguez, A., Dubois, B., Edvardsson, D., Feldman, H.,
TSP-1 expression. Nature Communications, 5, 4294. https://doi. Fratiglioni, L., Frisoni, G. B., Gauthier, S., Georges, J., Graff, C., Iqbal,
org/10.1038/ncomms5294 K., Jessen, F., Johansson, G., Jönsson, L., … Zetterberg, H. (2016).
Vasile, F., Dossi, E., & Rouach, N. (2017). Human astrocytes: Structure Defeating Alzheimer's disease and other dementias: A priority for
and functions in the healthy brain. Brain Structure and Function, European science and society. The Lancet Neurology, 15, 455–532.
222, 2017–2029. https://doi.org/10.1007/s00429-017-1383-5 https://doi.org/10.1016/S1474- 4 422(16)00062- 4
Verkhratsky, A., & Butt, A. M. (2018). The history of the decline and Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F.,
fall of the glial numbers legend. Neuroglia, 1, 188–192. https://doi. Silverstein, S. C., & Husemann, J. (2003). Adult mouse astrocytes de-
org/10.3390/neuroglia1010013 grade amyloid-beta in vitro and in situ. Nature Medicine, 9, 453–457.
Verkhratsky, A., Marutle, A., Rodríguez-Arellano, J. J., & Nordberg, A. Wyssenbach, A., Quintela, T., Llavero, F., Zugaza, J. L., Matute, C., &
(2015). Glial asthenia and functional paralysis: A new perspective Alberdi, E. (2016). Amyloid beta-induced astrogliosis is mediated by
on neurodegeneration and Alzheimer's disease. The Neuroscientist: beta1-integrin via NADPH oxidase 2 in Alzheimer's disease. Aging
A Review Journal Bringing Neurobiology, Neurology and Psychiatry, 21, Cell, 15, 1140–1152.
552–568. https://doi.org/10.1177/1073858414547132 Xiu, J., Nordberg, A., Zhang, J. T., & Guan, Z. Z. (2005). Expression of
Verkhratsky, A., & Nedergaard, M. (2018). Physiology of astroglia. nicotinic receptors on primary cultures of rat astrocytes and up-
Physiological Reviews, 98, 239–389. https://doi.org/10.1152/physr regulation of the alpha7, alpha4 and beta2 subunits in response
ev.00042.2016 to nanomolar concentrations of the beta-amyloid peptide(1–42).
Verkhratsky, A., Olabarria, M., Noristani, H. N., Yeh, C. Y., & Rodriguez, J. Neurochemistry International, 47(4), 281– 290. https://doi.
J. (2010). Astrocytes in Alzheimer's disease. Neurotherapeutics: the org/10.1016/j.neuint.2005.04.023
Journal of the American Society for Experimental NeuroTherapeutics, Yang, Z., & Wang, K. K. (2015). Glial fibrillary acidic protein: From in-
7, 399–412. https://doi.org/10.1016/j.nurt.2010.05.017 termediate filament assembly and gliosis to neurobiomarker.
|
324 KUMAR et al.
Trends in Neurosciences, 38, 364– 374. https://doi.org/10.1016/

j.tins.2015.04.003 How to cite this article: Kumar, A., Fontana, I. C., & Nordberg,
Yu, W. F., Guan, Z. Z., Bogdanovic, N., & Nordberg, A. (2005). High selec-
A. (2023). Reactive astrogliosis: A friend or foe in the
tive expression of alpha7 nicotinic receptors on astrocytes in the
brains of patients with sporadic Alzheimer's disease and patients pathogenesis of Alzheimer’s disease. Journal of Neurochemistry,
carrying Swedish APP 670/671 mutation: A possible association 164, 309–324. https://doi.org/10.1111/jnc.15565
with neuritic plaques. Experimental Neurology, 192, 215–225.

Journal of Neurochemistry - 2021 - Kumar - Reactive Astrogliosis A Friend or Foe in The Pathogenesis of Alzheimer S

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Received: 30 October 2021 Revised: 13 December 2021 Accepted: 15 December 2021

Reactive astrogliosis: A friend or foe in the pathogenesis of

Amit Kumar1 | Igor C. Fontana1 | Agneta Nordberg1,2

Journal of Neurochemistry. 2023;164:309–324. |

Trends in Neurosciences, 38, 364– 374. https://doi.org/10.1016/

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Journal of Neurochemistry - 2021 - Kumar - Reactive Astrogliosis A Friend or Foe in The Pathogenesis of Alzheimer S

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Journal of Neurochemistry - 2021 - Kumar - Reactive Astrogliosis A Friend or Foe in The Pathogenesis of Alzheimer S

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Received: 30 October 2021 Revised: 13 December 2021 Accepted: 15 December 2021

Reactive astrogliosis: A friend or foe in the pathogenesis of

Amit Kumar1 | Igor C. Fontana1 | Agneta Nordberg1,2

Journal of Neurochemistry. 2023;164:309–324. ﻿ |

Trends in Neurosciences, 38, 364–­ 374. https://doi.org/10.1016/​

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Journal of Neurochemistry. 2023;164:309–324. |

Trends in Neurosciences, 38, 364– 374. https://doi.org/10.1016/