142019 [Alzheimer’s dsease, metal ions and metal homeostatic therapy! Trends in Pharmacological Sciences Published: Jur DOI: hitps://doi.org/10.1016)j.tips. % Plumx Metrics Mounting evidences support the idea that endogenous ‘biometals’, such as copper, iron, zinc and exogenous ones such as aluminum, can be involved as factors or cofactors in the etiopathogenesis of a variety of neurodegenerative diseases. Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. In AD, the process of B-amyloid (AB) misfolding and plaque aggregation is greatly influenced by alterations in the homeostasis of the aforementioned metal ions. Here, we discuss the most recent evidences that associate metal ion dyshomeostasis with the development of AD. As for aluminum, a role for this ion in AD pathogenesis is still controversial. Thus, here, we also critically review new findings that argue for and against the ‘aluminum hypothesis’. Finally, itis discussed how therapeutic strategies aimed at restoring metal homeostasis can delay and modify the progression of AD-related neurodegeneration. Introduction Alzheimer's disease (AD) is a devastating neurological condition with no disease-modifying therapy available so far. The pathological hallmarks of AD are brain deposition of B-amyloid (AB) in senile plaques (SPs) and the appearance of neurofibrillary tangles (NFTs) made of hyperphosphorylated itein (Box 1). < > hitpshwww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 as,142019 [Alzheimer’s dsease, metal ions and metal homeostatic therapy! Trends in Pharmacological Sciences Box 1 Molecular mechanisms involved in the pathogenesis of Alzheimer's disease Alzheimer's disease is characterized by extracellular deposition of the B-amyloid (AB) fibrils in the senile plaques (SPs) and by intraneuronal aggregates of neurofibrillary tangles (NFTs) made of paired helical filaments (PHFs) of the hyperphosphorylated tau protein (Figure I). by ‘Norma! beain a “AD bain i Sonde pques | = = af _, — | ae Figure | Pathological hallmarks of AD. Extracellular deposition of the f-amyloid fibrils in the senile plaques (SPs) and intraneuronal aggregates of paired helical filaments (PHFs) of the hyperphosphorylated tau protein in neurofibrillary tangles (NFTS) represent the hallmark pathogenic features of the disease, and their observation in @ postmortem examination is still required for a diagnosis of AD. In accordance with the amyloid cascade hypothesis, it has been proposed that AB aggregation follows a sequence by which the accumulation of soluble AB is followed by the appearance of low molecular weight oligomers that rapidly associate in higher order aggregates and finally precipitate to form senile plaques. AP aggregation is greatly influenced by all the metal fons (e.g. Al, Cu, Fe and Zn) that are found in both the core and rim of the AD senile plaques. View Large Image | Download (PPT) Senile plaques and neurofibrillary tangles are mainly present in brain regions “ ntorhinal cortex, hippocampus, basal forebrain and amygdala) that are involved in arning, memory and emotional behavior. The discovery of AB in SPshasle < 1e > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 2188sie2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences formulation of the ‘amyloid cascade hypothesis’, which revolves around the concept that an imbalance in AB metabolism leads to abnormal aggregation and deposition of the peptide, a process that causes neuronal death, synaptic dysfunction and, ultimately, dementia [45, 81]. AD is also associated with tau pathology [82]. The physiological role of tau is to control the assembly of neuronal microtubules, thereby providing an essential element for the stabilization of the neuronal cytoskeleton, a key system to maintain structural integrity and axonal transport. In AD, the hyperphosphorylation of the tau protein promotes the derangement of microtubules and the formation of tangles of aggregated tau, an additional process that triggers neuronal death [83, 84]. Interestingly, AB and tau dysmetabolism can influence each other and enhance their relative contribution to the AD-related neuronal loss [85, 86] Metal ion dyshomeostasis is a well-recognized cofactor in several neurodegenerative disorders [1, 2]. Metals are essential for life and have a central role in many biochemical pathways. Genetic dysfunction, environmental exposure, ageing, inadequate dietary intake and drug interaction can all induce an alteration in their homeostasis leading to deleterious effects and neurotoxicity (Figure 1) Genetic stanton Gente dysiunaton EEnwonmental expocure Inacequate cet intake Aaong sou tone rg intraction Aecumation A Detoenoy TEND PT rcs Figure 1 Schematic representation of the factors affecting the delicate balance between metal ion accumulation and deficiency. View Large Image | Download (PPT) Metal dyshomeostasis, especially in the case endogenous metal ions such as copper (Cu), iron (Fe), zinc (Zn) or the exogenous contaminant aluminum (Al), has attracted the interest of researchers investigating the etiology of a variety of neurodegenerative conditions and the enesis of AD in particular [1, 2]. As for AD, the misfolding process, associated with a3 < > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 3108sien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences aggregation, is greatly influenced by the metal ions (j.e. Al, Cu, Fe and Zn) that are found in both the core and rim of the AD senile plaques (3, 4, 5, 6, 7, 8] (Table 1). Table 1 Metal levels in patients er's disease compared with healthy individuals Location Zincwgg' (uM) Copperugg”' (uM) trong" (uM)" Plaque rim 67 (1024)? 23.(357)° 52 (938)" Plaque core 87 (1327) 30 (474) 53 (951) Tolal senile plaque 69 (1055)" 25 (393)° 53 (940)" Alzheimer's neuropil 1 (786)" 19 (304) 39 (695) Contro! neuropil 23 (346) 4(69) 19 (338) a Numbers in brackets represent molar concentrations, which were converted with the assumption of a sample density equivalent to 1 g em" b P< 0.05 (plaque values compared with neuropils from patients with Alzheimer's disease). ¢ P<0.05 (neuropils from patients with Alzheimer's disease compared with neuropils from control individuals). Reproduced, with permission, from Ref. [17]. Open table in a new tab In recent years, the interest for the role of metal dyshomeostasis as a pathogenic factor for AD has been strongly revived after the publication of several key reports indicating that therapeutic strategies that restore metal ion homeostasis in the brain of both AD patients and AD transgenic mice are able to reverse AB aggregation, dissolve amyloid plaques and delay the AD-related cognitive impairment [9, 10, 11] hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 4108sien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences Here, we review the most recent evidences linking metal ion imbalance and AB aggregation. We also examine the participation of the AI-AB complex as a cofactor in the pathogenesis of AD. A critical review of the recent findings on the deleterious effects of this complex might provide new arguments for a debate that has animated the AD field for years. Finally, we discuss new potential approaches for the treatment of AD that are based on restoration of metal homeostasis in the brain. Role of metal homeostasis in AD The proactive role of metal ions in stimulating AB aggregation, in addition to their interaction modalities with the AB peptide, has been widely investigated in vitro (reviewed by Refs [12, 13]). Most of the glutamatergic synapses in the cerebral cortex, but not all, co-release Zn along with glutamate [14, 15, 16, 17]. This cation has been indicated to have a primary role in AD owing to its efficacy to induce fast precipitation of AB together with its capability to build up protease-resistant ‘non-structured’ aggregates [18]. Furthermore, studies on AD animal models have also shown that genetic ablation of synaptic Zn greatly reduces the amount of amyloid plaques [19] and several studies indicate that compounds affecting Zn homeostasis can decrease AB deposition in the brain [9, 10, 20}. Noteworthy in this regards, a recent paper has shown that the release of synaptic Zn* facilitates the oligomerization of AB and its sequestration in the synaptic cleft [21], suggesting a Potential mechanism for the synaptic deficits observed in AD. Finally, expression levels of Zn transporters, such as ZnT1, ZnT4 and ZnT6, were discovered to be altered in the brain of individuals affected by mild cognitive impairment (MCI) and AD [22] Like Zn, Cu is synaptically released [23] and acts as a potent mediator of AB aggregation under conditions of mild acidosis [24, 25]. Compared with Zn, Cu has the additional property of producing strong extra-mitochondrial oxidative stress [26]. Several studies have indicated that, because of their redox-active nature, transition metal ions such as Cu and Fe can interact with AB catalyzing the generation of H202 through a reduction process that uses O, and bioavailable reducing agents such as cholesterol, vitamin C and catecholamines [27]. Thus, in the absence of sufficient detoxifying enzymes such as catalase and glutathione peroxidase, H20, can lead to further generation of hydroxyl radicals through the Fenton reaction (Box 2) with relevant consequent neurotoxic effects. = Box2 anton reaction < > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 siesie2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences Fe?* + H202 — Fe*t + OH + OH”. This is the iron-salt-dependent decomposition of dihydrogen peroxide, generating the highly reactive hydroxyl radical, possibly via an oxciron (IV) intermediate. Addition of a reducing agent, such as ascorbate, leads to a damaging cycle that targets biological molecules Alteration of intracellular [Cu], homeostasis has been implicated in AD [28, 29] given that [Cul activates phosphoinositol-3-kinase-mediated protein kinase pathways, thereby increasing the secretion of matrix metalloproteinases (MMPs), a class of enzymes that degrades AB [30]. According to this model, the amyloid precursor protein (APP) triggers Cu depletion in the AD brain as APP binds to Cu and act as a Cu chaperone favoring the efflux of the ion. Such a model is substantiated by findings in APP-knockout mice, in which Cu levels are found to be increased in the cerebral cortex [31], whereas an overexpression of APP promotes a significant reduction of [Cu]; in the brain of AD transgenic mice. Although it is intriguing to consider Cu and Fe as important players in AD pathogenesis given their pro-oxidant activity, it should also be considered that pathological conditions associated with increased levels of Cu and Fe (i.e. Wilson's disease) do not show enhanced deposition of AB plaques indicating that the metals might be necessary but are certainly not sufficient to cause a multifactorial pathology like AD (for more details see Box 3). Metal, homeostasis and AD Intraneuronal Zn homeostasis is controlled by a balance between influx, buffering and extrusion. Most Zn enters neurons through voltage-sen: /e Ca channels and Ca-permeable ionotropic glutamate receptors [87]. Sequestration and buffering is largely controlled by metallothioneins (MTs), mitochondria, zincosomes and lysosomes [73, 88, 89, 90, 91]. MTs are present in the central nervous system in three isoforms (MT-1, MT-2 and MT-3). MT1 and MT2 are expressed in astrocytes, whereas MT-3 is expressed predominantly in neurons [92]. Zn2* is bound to MTs, but this binding can be readily modulated by changes in the redox state of the two Zn?*/Cys cluster regions and endogenous (superoxide and peroxynitrites) or exogenous oxidants promote harmful Zn release from these proteins [72, 93, 94]. — tus, MT-3 could be a major source of toxic Zn inside neurons [95]. Mitocho ly > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 eeesie2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences sequestered Zn can be re-released into the cytosol in a Ca-dependent manner, suggesting a potentially injurious interplay between Zn and Ca dyshomeostasis [91]. Postmortem studies have shown that the cation is elevated within mature AB plaques (Table 1), whereas plaque formation is dramatically reduced in AD transgenic mice lacking vesicular presynaptic Zn or in AD animals treated with Zn chelators [9, 10, 19, 20} Cu homeostasis is controlled by MTs and by the activity of a Cu transporter ATPase [96]. lonic Cu is released into the cleft following postsynaptic stimulation of the N- methyl-p-aspartate (NMDA) receptor [97, 98] and is concentrated into postsynaptic vesicles by the Menkes Cu7aATPase [98] The amyloid precursor protein, APP, can act as a copper transporter [99]. APP has two copper binding sites, including one in the AB peptide sequence [24, 100] and APP overexpression in transgenic mice has been shown to reduce brain Cu levels [101, 102]. Proteins of similar structure, such as APLP1 and APLP2, also have Cu binding domains and might similarly promote Cu efflux [31, 99, 100]. Fe homeostasis is controlled by the Fe transport protein transferrin (Tf), a serum glycoprotein that binds two atoms of Fe [103], and by ferritin. Several lines of evidence suggest that Fe dyshomeostasis and Fe-induced oxidative stress have some role in the pathogenesis of AD. Abnormal levels of Fe, ferritin and Tf have been reported in the hippocampus and cerebral cortex of AD brains [104]. Furthermore, in brain areas more vulnerable to AD-related neurodegeneration, Fe has been shown to accumulate at a pace that is not matched by similar levels of ferritin production [105] Ais largely present in food and beverages such as tea [106] and in drugs like the antiacids, Despite its ubiquitous presence, only 0.06-0.1% of the ingested Al is absorbed across the gastrointestinal tract [107]. Al uptake is limited by the presence of certain dietary components (such as citrate) that complex the ion [108] and by the competition for uptake exerted by other ions such as Ca, Mg and Si [109]. To date, it is not completely understood whether Al can enter the brain and, if it does, by which echanism, Some authors have suggested that Al can gain access to the br" srmeating the blood-brain barrier (BBB) through the activation of several ec < 1. > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 Tiesie2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences that respect, transferrin-mediated transport of Al has been suggested [110], whereas other authors have indicated a possible transporting role for the monocarboxylate transporter (MTC), a proton co-transporter that is located at both the luminal and abluminal surfaces of the BBB [111, 112]. Finally, recent findings have suggested that structural and functional pathological changes of the BBB might promote Al accumulation in the AD brain (112, 113, 114, 115, 116]. Anew role for Al in AD? In the context of AD-related metal dyshomeostasis, an interesting albeit controversial angle is offered by the Al dysmetabolism. A pathogenic role for Al in AD has been hypothesized since the 70s; however, such a model has been partially discredited mostly because of the paucity of reliable studies and data on Al chemical speciation in addition to an incomplete understanding of the complexity of Al chemistry in biological systems. Al is known to be the most abundant metal ion in the Earth's crust and there are few doubts about its high toxicity for humans and animals [32]. Altered brain levels of Al have been associated with a specific neurological condition such as fatal dialysis-linked encephalopathy (DE) that is due to Al-contaminated water in dialysate solutions [33] However, such iatrogenic disease is not associated with AD-like pathology [34]. Although Al contamination of dialysates has been overcome by the use of deionised water, new cases of subacute DE are still reported because of Al-containing drugs are often prescribed to control hyperphosphatemia and gastric problems in patients with chronic renal failure [34, 35]. Overall, the pathological changes found in DE and subacute Al encephalopathy support the idea that Al can be neurotoxic whenever the physiological excretion of the metal is impaired. By contrast, these findings also indicate that, again, Al per se is not a cause sufficient to promote AD because the neuropathological and functional hallmarks of DE and subacute Al encephalopathy in patients with a history of long term dialysis do not overlap with those observed in AD patients [36, 37, 38]. Thus, despite the established neurotoxic activity of the ion, the ‘aluminum hypothesis’ for AD continues to be a cultural anathema to most neuroscientists. After so many years of debate we suggest a fresh look at the whole issue and considering of new evidence that could somehow ‘re- evaluate’ the importance of this metal as a cofactor in AD. In our opinion, an unbiased look at the somnloxity of Al chemistry in biological systems could reconcile many conflicting data reported in rature [38, 40]. One example of such controversy is given by the issue of Alder ¢ 1A, hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 siesien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences brains. Several laboratories have documented Al accumulation in AD brains by using Laser Microprobe Mass Analysis (LAMMA) demonstrating abnormal high Al concentrations located mostly within the AD neurofibrillary tangles [3, 5, 8]. However, a recent interesting study by Miller and colleagues [41] employed synchrotron-base infrared and X-ray imaging to investigate metal deposition in brains of AD patients. They reported that, whereas Cu, Zn, and Fe can be detected, no Alwas found in the senile plaques. These results are not surprising given the specific aspects of the. technique employed in the study. In this study, Al was, in fact, part of the coating of the substrate where biological samples were deposited and the machine was indeed set to be blind to the analytical identification of Al. In other words, the system was selectively set to ‘ignore’ Al. Although Al is certainly not the only metal involved in AD pathological features, itis also true that the whole AD field is still very far from having an exhaustive understanding of the molecular determinants involved in the disorder. Several evidences indicate that Al can contribute to both tau- and AB-dependent pathology. Al, a highly reactive element, can promote tau-dependent pathology as the ion can easily cross-link hyperphosphorylated proteins [42]. Moreover, using intracerebral injections of pair helical tau filaments with and without Al, Lee and Trojanowski indicated that this metal is shown to co-localize with several proteins that have a key role in AD like AB, ubiquitin, ACT, and ApoE [43, 44] (Figure 2) Microtubules wd 0 | 0 ae) “071 *o ° \ Pp —0H Morotubules ° | ra] 0 TRENDS in Phammacoloial Sciences hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 sie142019 [Alzheimer’s dsease, metal ions and metal homeostatic therapy! Trends in Pharmacological Sciences Figure 2 Alas a possible modulator of tau pathology. Sites of possible interaction between Al and hyperphosphorylated tau protein that is associated with the cytoskeletal microfilaments and the neurofibrillary tangles found in AD. View Large Image | Download (PPT) The idea that Al dyshomeostasis might be a cofactor for AD also fits well with the ‘amyloid cascade hypothesis’, According to this theory, the pathological production of AB peptide leads to synaptic dysfunction and ultimately dementia (see also Box 1). More recent studies indicate that amyloid dysmetabolism synergistically promotes the development of tau-dependent pathology and the formation of neurofibrillary tangles [39]. Furthermore, new findings in AD research strongly support the idea that the severity of AD-related neuronal loss and dementia is largely mediated by the soluble forms of Af oligomers, rather than fibrillar and insoluble AG deposits [45]. In both AD subjects and AD animal models [46, 47], there are compelling evidences indicating that brain levels, of soluble AB species (and hyperphosphorylated tau) correlate better with cognitive decline rather than plaque density [48]. Furthermore, intraneuronal accumulation of such soluble AB oligomers might also have a critical role in AD pathogenesis (reviewed in Ref, [49]) given that AD-related synaptic deficits are specifically mediated by these oligomers [50, 51}. Studies in AD brain preparations have shown that the formation of AB oligomers is initiated intracellularly rather than in the extracellular space [52], a phenomenon that has been also validated in AD transgenic mice [53]. Intraneuronal AB deposition in AD target areas, such as the hippocampus and the entorhinal cortex, of subjects with MC! supports the idea that intraneuronal accumulation of AB acts as an early mediator of synaptic dysfunction and cognitive impairment [54]. Intriguingly, in line with this up-to-date revision of the ‘amyloid cascade’ theory, our recent results indicate that Al, when conjugated with AB, can have a role in promoting a sort of ‘freezing’ of the peptide in its oligomeric state, thereby favoring the formation and assembly of the most dangerous and neurotoxic amyloid species [55] (Figure 3). hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 10108142019 ‘Alaheimer’ disease, metal ions and metal homeostatic therapy! Trends in Pharmacological Sciences AL-Fo Ap-zn arge population. otal) Figure 3 AB when conjugated with Al undergoes structural changes. Transmi ion electron microscopy (TEM) of AB and ‘Ag-metal complexes. Many short and irregular protofbrillar structures appeared in the AB sample. The AG-Al complex {riggers the appearance ofa large population of small oligomers whereas the other complexes (AB-Cu, AB-Fe, AB-Zn) form mainly unstructured filaments, View Large Image | Download (PPT) Several recent studies have shed some light on novel pathogenic pathways by which Al dyshomeostasis can possibly favor AD progression (www.alzforum.com). New findings have provided a detailed characterization of the jn vitro conformation and aggregation changes stimulated by Alon different AB fragments and, in particular, on human AB [55, 56]. Furthermore, when compared with other metal ions such as Fe, Zn and Cu, Al seems to be very effective in promoting in vitro ‘structured’ aggregation of AB associated with particularly high neurotoxicity [56]. When conjugated with Al, AB undergoes a spontaneous change in the structural conformation that leads to an increase in its surface hydrophobicity that is associated with solvent-exposed hydrophobic patches. Such an AB-Al metal complex shows a dramatic reduction in the sequestration in the brain microcapillaries and (indeed, not surprisingly) an increased high permeability across the blood— brain barrier (BBB), a phenomenon that is leading to intracerebral accumulation of AB-Al [57]. Comparative studies on the aggregation states of both human (hAB) and rat B amyloid (rAB) in the ce or absence of Al have shown that AB-Al complexes are capable of increase eg sompared with AB itself. These studies have also shown that the metal seems p © at > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 niessien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences efficient in changing the morphology of hAB aggregates. This phenomenon is most likely to be due to the different amino acid sequence of hAB compared with rAB, a change that seems to be essential for promoting different levels of toxicity when the two amyloid proteins are conjugated with Al [58]. Thus, the different aggregational behavior of rat and human amyloids in the presence of Al emphasizes the close relationship between the morphology of AB aggregates and their cell toxicity [55]. One possible explanation comes from experiments in human neuroblastoma cells where Al seems to promote AB oligomerization and dramatically increase cellular toxicity. In a set of microarray and real-time PCR experiments, in which we investigated the gene expression profile of human neuroblastoma cells (~35 000 genes) treated with various AB-metal complexes (AB-Cu, AB-Zn, AB-Fe and AB-Al), AB alone or the metal ions themselves, we observed that the AB-Al complex is able to produce a selective upregulation of a well known series of AD-related genes such as the APLP1 and APLP2 (amyloid precursor-like protein-1 and -2), MAPT (microtubule-associated protein tau) and APP genes (Drago et al., unpublished). Moreover, in functional experiments, we also found that in neuronal cell cultures exposed to various AB-metal complexes (AB-Cu, AB-Zn, AB-Fe and AB-Al) only the AB-Al complex is able to alter glutamate-driven [Ca] rises [59]. In the same study, AB-Al was also found to inhibit the oxidative respiration in isolated rat brain mitochondria [59]. These results are in line with a previous study that indicated that extracellular applications of ‘spherical’ oligomeric forms of ABy_42 and several other disease-related amyloidogenic proteins can cause disruption of [Ca*] [60], whereas equivalent amounts of monomeric and fibrillar forms of AB are unable to induce any detectable effect. Our mitochondrial studies are in agreement with studies from other laboratories where ABy_42 was found capable to induce a decrease in state 3 respiration, a phenomenon that is strongly exacerbated when the peptide is conjugated with Al [61]. Finally, signs of Al dyshomeostasis were also recently found in a triple transgenic AD mouse, the 3xTg-AD, that expresses mutant APP, PS1 and tau and is, therefore, considered to recapitulate the hallmarks of AD pathology [62]. In that study, experiments employing mass spectrometry indicate that, when compared with the distribution of other AD-relevant metals (Zn, Cu and Fe), Al is the only metal ion that is significantly increased in the cortex of 14-month-old 3xTg-AD mice [59]. Altogether, these data suggest a potentially intriguing new role for Al in AD pathogenesis. Metal homeostatic therapy: a new therapeutic approach hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 12188sien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences Although metal ion dyshomeostasis is certainly not the only trigger of the disease, therapeutic interventions aimed at restoring metal homeostasis remain strong candidates as disease-modifying strategies for AD treatment, What is emerging from recent data obtained by several laboratories is that, more than aiming at chelating strategies, research should be focused on molecules (called by some authors, metal-protein attenuation compounds [MPACs}) that are capable of sequestering Cu and Zn from both amyloid plaques and the synaptic cleft and act as Cu ionophores to compensate the AD-related [Cu] deficiency [12]. However, it should also be emphasized that pinpointing a single metal as the major culprit of the disease seems to be less productive. The jury is out about which metal ion induces most aggregation and which induces most toxicity, but it should be understood that a change in the brain level of a single metal ion can upset the whole metal pool, resulting in a relevant complex metal imbalance inside and outside of the central nervous system. Thus, itis likely that upon such a ‘domino effect’, pharmacological and/or pathological alteration in the level of a single metal can eventually affect the whole distribution pattern of many others (Figure 4). 00 wat ie Figure 4 Homeostatic interplay between brain metals: the domino effect. Bar graph depicts the concentrations of Ca, Cu, Fe, Zn and Alin the brain of GD-1 adult mice fed for'3 months with a Cu-adequate or a Cu-deficient diet, Note how all the metal lovels aro strongly affected by the modification ofthe dietary intake of a single metal (Cu), highlighting the close Interaction between different metal distributionistorage pathways. * P< 0.01, *P< 0.05 versus contro View Large Image | Download (PPT) vast few years, a convergence of pharmacological studies in AD animal models "~~ me metal homeostatic strategies and achieved important neuroprotective effects. A < \D > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 saesien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences related Cu dyshomeostasis, it has been reported that a small chelating molecule such as apo- cyclen is able to sequester the synaptic Cu bound to AB and also inhibits both AB oligomerization and neuronal death while actively promoting AB cleavage [63]. An additional study has indicated that, as Cu influences the development of tau-dependent pathology [64], APP/PS1 transgenic mice treated with the Cu-ligand pyrrolidine dithiocarbamate showed an increase in brain Cu levels, which activates Akt-mediated GSK3 phosphorylation, a process that leads to a substantial decrease in tau phosphorylation and attenuation of cognitive deficits. Furthermore, Crouch and colleagues [65] have recently shown that increasing [Cu?*]; bioavailability in the brain can restore cognitive function by blocking the accumulation of neurotoxic AB trimers and phosphorylated tau. Tetramine derivatives have also been shown to reduce brain Cu levels in the brain cortex without affecting the blood levels of the cation [66]. Moreover, a lipophilic chelator (DP109) that can trap Ca and Zn at the cell membrane level has also been found capable reducing brain amyloid deposition in an AD transgenic model {20}. Finally, a great interest has been generated in the beneficial effects of 5-chloro-7-iodo-8- hydroxyquinoline (clioquinol; CQ), a Cu and Zn ionophore that is able to reduce the size and number of AB plaques in transgenic AD mice [10]. PBT2, a second-generation 8-OH quinoline derivative of CQ has also been shown to promote neuroprotection and delay cognitive impairment in an AD transgenic model [9]. The proposed mechanism by which CQ can promote neuroprotective effects is by enhancing intracellular Cu and Zn uptake, thereby acting as an ionophore that favors the clearance of these ions from parenchymal amyloid plaques and the synaptic space [67]. According to the model, CQ can also restore intracellular Cu levels and induce the upregulation of matrix metalloproteases MMP-2 and MMP-3, ultimately promoting the digestion of amyloid oligomers [68] (Figure 5). leFigure thumbnail gr5 Figure 5 Neuroprotective effects of Clioquinol. Clioquinol (CQ) has b n recently proposed as disease-modifying drug for AD. CQ seems to have ionophore activity that favors the entrance Into cells of Zn and Cu. Cu entry in particular determines, ‘the activation of metalloproteases (MMP) resulting in the degradation of AB. In addition, CQ could also remove Cu and Zn that is sequestered in senile plaques (SP), thereby reducing the oligomerization of the peptide. Abbreviation: SMON, syndrome subacute myelo-optico-neuropathy. View Large Image | Download (PPT) hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 aiesien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences Indicating the complexity of restoring biometal homeostasis, we have found that CQ, after conjugation with AB-metal complexes (Cu and Zn), is unexpectedly able to promote in vitro aggregation and fibrillogenesis of human A8 rather than dissolution of the fibrils [69]. By contrast, other cell culture studies have shown that CQ-Cu complexes can permeate the cells and markedly inhibit AB deposition (67). Finally, recent studies indicate that CQ (and probably CQ-related compounds) might also favor the buffering of synaptic Zn and inhibit the deposition of toxic AB oligomers in the synaptic cleft [9, 21, 70]. No matter what the net result, it is encouraging to note that clinical trials have shown that both CQ and the CQ derivative PBT2 can be safely used in AD patients and attenuate some of the AD- related cognitive deficits (70, 71]. Itis also intriguing to consider that, because Zn-dependent neuronal death is largely due to intracellular mobilization of the cation from sources such as metallothioneins (MTs), mitochondria, and lysosomes, [19, 72, 73, 74, 75, 76], it should be pointed out that the potential neuroprotective role of a new class of low affinity and cell-permeable Zn chelators able to buffer intraneuronal Zn?* rises, thereby preventing Zn?* neurotoxicity and/or the early intraneuronal aggregation and oligomerization of toxic AB species, remains to be explored. Conclusions and future perspectives Undoubtedly, aging remains the most important risk factor for the development of neurological disorders and AD in particular, suggesting that these conditions are likely to be the result of cumulative metabolic impairment occurring over decades of life. Metal ion dyshomeostasis per se is probably not the sole or even the primary cause of AD; however, in the context of an aging brain it might have a relevant role in the development and progression of the disease. Aging, for instance, is associated with increased levels of oxidative stress [77], a factor that might also perturb the Cu/Zn homeostasis, given that MTs tend to be overexpressed in the aging brain [78]. In rats, the expression of the gene encoding for the MT neuronal isoform, MT3, is increased in neurons obtained from the aging hippocampus compared with young controls [79]. Notably, MTs are potent antioxidants and protective factors against stress conditions. MT-increased expression in the aging brain might simply reflect a protective endogenous response to a sub-chronic state of inflammatory and/or oxidative stress. By contrast, it is possible that the neuroprotective actions of in be overridden by a concomitant increase in reactive-oxygen-species-driven [7"" ulation. As in the aging brain (and even more so in the AD brain), there is an ine sin > hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 15i08sien2019 ‘Azheimersdsease, metal lons and meal omeosate therapy Tends in Pharmacological Sciences level of inflammatory cytokines; a chronic upregulation of MTs can lead to higher availability of intracellularly releasable Zn?" in response to oxidative stress [78, 80]. In that respect, itis interesting to note that neurons obtained from 3xTg-AD mice respond to oxidative stress with an enhanced mobilization of [Zn?*]; compared with control mice [75]. in summary, the ‘metal hypothesis of Alzheimer's disease’, with the addition of the concept that the neuropathogenic effects of AB in AD are promoted by (and possibly even dependent on) the conjugation of the peptide with selected metals, seems to be a very workable hypothesis. Increasingly sophisticated pharmaceutical approaches are now implemented to attenuate abnormal interactions between AB and metals without causing a systemic disturbance on their systemic levels. The whole AD field will be soon in a position to verify whether addressing metal dyshomeostasis can have a strong therapeutic potential in AD. 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ScienceDirect Access this article on ScienceDirect hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0185-5147(09)00088-1 anes,142019 Figure | Pathological hallma... Figure 1 Schematic represe... Figure 2 Al as a possible m... Figure 3 AB when conjugat... Figure 4 Homeostatic interp... Figure 5 Neuroprotective eff... Tables Table 1: Metal levels in patients with Alzheimer's disease compared with healthy individuals Related Articles The Cellular Phase of Alzheimer's Disease De Strooper et al. Cell, February 11, 2016 In Brief + Full-Text * PDF Open Archive Sorting Out Presenilins in Alzheimer’s Disease Wolfe et al. Cell, June 30, 2016 In Brief » Full-Text * POF Open Archive ___ue Microglia Type Associated with Restricting Development of Alzheimer’s Dise ‘Shaul et al. < hitpswww-cel comftrends/pharmacologica-sclencesfultex'S0165-5147(09)00088-1 > anus,142019 [Alzheimer’s dsease, metal ions and metal homeostatic therapy! 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