Anatoly V Skalny

Michael Aschner

Yueming Jiang

Yordanka G Gluhcheva

Yousef Tizabi

Ryszard Lobinski

Alexey A Tinkov
email: tinkov.a.a@gmail.com

Molecular mechanisms of aluminum neurotoxicity: Update on adverse effects and therapeutic strategies

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

that are currently not widely used thus reducing the risk of vaccine-associated Al exposure (Goullé and Grangeot-Keros, 2020).

Being a non-essential element, Al was shown to be toxic for humans [START_REF] Exley | Human exposure to aluminium[END_REF], resulting in adverse health effects [START_REF] Crisponi | Human diseases related to aluminium overload[END_REF] including bone pathology [START_REF] Klein | Aluminum toxicity to bone: a multisystem effect?[END_REF] and breast cancer [START_REF] Darbre | Aluminium and breast cancer: sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology[END_REF]. Our data also demonstrated the association between obesity [START_REF] Tinkov | Aluminium levels in hair and urine are associated with overweight and obesity in a non-occupationally exposed population[END_REF], laboratory markers of metabolic syndrome and Al exposure markers [START_REF] Skalnaya | Hair trace elements in overweight and obese adults in association with metabolic parameters[END_REF]. However, the existing data on adverse effects of Al exposure are limited [START_REF] Krewski | Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide[END_REF].

Recent studies have demonstrated that the brain may be considered as the target for Al toxicity, resulting in neurodegenerative [START_REF] Exley | Human exposure to aluminium[END_REF][START_REF] Shaw | Aluminum-induced entropy in biological systems: implications for neurological disease[END_REF] and neurodevelopmental disorders [START_REF] Blaylock | Aluminum induced immunoexcitotoxicity in neurodevelopmental and neurodegenerative disorders[END_REF]. Recent detailed studies by Exley and the coauthors have highlighted the association between brain Al accumulation and neurological disorders including Alzheimer's disease, multiple sclerosis and autism spectrum disorder [START_REF] Exley | Aluminum-induced "mixed" cell death in mice cerebral tissue and potential intervention[END_REF][START_REF] Mirza | Aluminium in brain tissue in familial Alzheimer's disease[END_REF][START_REF] Mold | Aluminium in brain tissue in autism[END_REF]. Speciation analysis using hyphenated techniques demonstrated that Al exposure induces a specific bioligand response in Al-exposed neuronal cells [START_REF] Połeć ; Pawlak | Investigation of the aluminium binding in Al (III)-treated neuroblastoma cells[END_REF]. However, the particular mechanisms of Al neurotoxicity and their role in Al-associated neurological disorders are still debatable [START_REF] Morris | The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved?[END_REF]. This chapter will provide an update on the particular mechanisms of Al neurotoxicity that may be used as targets for development of therapeutic strategies.

Generally, the neurotoxic effect of Al exposure is mediated by its common toxic properties including prooxidant, proinflammatory, proapoptotic activity that are reported for a variety of cell lines and tissues, as well as more specific "neurotropic" effects namely interference with neurotransmitter metabolism and neuronal cytoskeleton.

Oxidative stress along with mitochondrial dysfunction (see next section) are involved in development of a variety of adverse effects of Al including neurotoxicity [START_REF] Kumar | Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review[END_REF]. The observed increase in brain lipid peroxidation under Al exposure (Ghorbel et al., 2016;[START_REF] Nehru | Oxidative damage following chronic aluminium exposure in adult and pup rat brains[END_REF][START_REF] Yuan | Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats[END_REF] was shown to be associ 2. Oxidative stress

U N C O R R E C T E D P R O O F
ated with a significant reduction in antioxidant enzyme activity, namely superoxide dismutase [START_REF] Nehru | Oxidative damage following chronic aluminium exposure in adult and pup rat brains[END_REF], catalase [START_REF] Nehru | Oxidative damage following chronic aluminium exposure in adult and pup rat brains[END_REF], glutathione peroxidase [START_REF] Sánchez-Iglesias | Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6-OHDA-induced model of Parkinson's disease[END_REF], glutathione reductase [START_REF] Nehru | Reversal of an aluminium induced alteration in redox status in different regions of rat brain by administration of centrophenoxine[END_REF], as well as glutathione-S-transferase (Bhalla and Dhawan, 2009). Alteration of glutathione system is also characterized by Al-induced decline in cerebral and cerebellar total, reduced, and oxidized glutathione levels (Anand and Nehru, 2006). In contrast to glutathione, data on involvement of thioredoxin system to Al-induced redox perturbations are insufficient, although recent study revealed a significant decrease in mitochondrial thioredoxin in aluminum chlorohydrate treated SH-SY5Y neuroblastoma cells [START_REF] Tsialtas | Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling[END_REF].

Al exposure was also shown to reduce mitochondrial Mn-SOD activity thus contributing to mitochondrial dysfunction (Kumar et al., 2009a,b). At the same time, certain studies demonstrated Al-induced increase in SOD activity and gene expression (Ali et al., 2014) that may also contribute to oxidative stress through overproduction of hydrogen peroxide, especially at low catalase and GPx activity. Inhibitory effect of Al on antioxidant system are likely mediated by Al-induced down-regulation of Nrf2/Keap1 signaling pathway (Yu et al., 2019a,b), whereas prevention of this inhibitory effect ameliorated prooxidant activity of the metal [START_REF] Wang | Chlorogenic acid protects against aluminium-induced cytotoxicity through chelation and antioxidant actions in primary hippocampal neuronal cells[END_REF].

In parallel with inhibition of antioxidant system, the role of Al in development of cerebral oxidative stress may be mediated by its impact on prooxidant systems. Particularly, exposure to Al was shown to increase cerebral level of inducible [START_REF] Bondy | Aluminum treatment induces nitric oxide synthase in the rat brain[END_REF] and endothelial NOS [START_REF] Mokhemer | Comparative study of the effect of chronic aluminium chloride administration on the expression of endothelial nitric oxide synthase in rat brain[END_REF] with a concomitant elevation of brain NO levels (Al-Olayan et al., 2015). The use of the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) significantly reduced Al-induced oxidative damage in brain, indicating a critical role of NOS induction in the prooxidant activity of Al [START_REF] Stevanović | The effect of inhibition of nitric oxide synthase on aluminium-induced toxicity in the rat brain[END_REF]. Al-induced alteration of vascular reactivity was shown to be associated with increased superoxide production from activated NADPH-oxidase [START_REF] Schmidt | Aluminum exposure for one hour decreases vascular reactivity in conductance and resistance arteries in rats[END_REF] due to up-regulation of NAD(P)H oxidase 1 and 2 mRNA expression [START_REF] Martinez | Aluminum exposure at human dietary levels promotes vascular dysfunction and increases blood pressure in rats: a concerted action of NAD (P) H oxidase and COX-2[END_REF]. Stimulatory effect of Al was observed in another enzymatic source of superoxide anion, xanthine oxidase, in liver [START_REF] Moumen | Aluminium increases xanthine oxidase activity and disturbs antioxidant status in the rat[END_REF] as well as various brain regions [START_REF] Sushma | Aluminium acetate induced oxidative stress in brain of albino mice[END_REF].

U N C O R R E C T E D P R O O F
In addition to enzymatic prooxidants, Al was capable of potentiating prooxidant effect of iron in neuronal cultures [START_REF] Xie | Intraneuronal aluminum potentiates iron-induced oxidative stress in cultured rat hippocampal neurons[END_REF]. This effect may also underlie a shift to ferroptosis in PC12 cells exposed to aluminium [START_REF] Cheng | Aluminum maltolate triggers ferroptosis in neurons: mechanism of action[END_REF]. It is also notable that co-exposure to Al and 6-hydroxydopamine enhanced 6-hydroxydopamine autooxidation-induced oxidative stress in brain mitochondrial preparations [START_REF] Sánchez-Iglesias | Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6-OHDA-induced model of Parkinson's disease[END_REF]. Moreover, Al is directly involved in the formation of highly reactive Al superoxide semi-reduced radical ion (AlO 2 2 +• ) [START_REF] Exley | The coordination chemistry of aluminium in neurodegenerative disease[END_REF]. Taken together, increased production of reactive oxygen species due to activation of enzymatic and non-enzymatic prooxidant systems and reduced antioxidant capacity of the cells (Fig. 1) result in Al-induced oxidative stress affecting neuronal protein structure and inducing redox-sensitive pathways. Mitochondrial dysfunction is considered as one of the first pathological responses to Al exposure in the cell, resulting in altered energy metabolism, oxidative stress, and apoptosis. Particularly, Al was shown to decrease mitochondrial electron transport chain through inhibition of complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), and complex IV (cytochrome oxidase) in rat cortex and midbrain, as well as cerebellum [START_REF] Sood | Curcumin attenuates aluminum-induced oxidative stress and mitochondrial dysfunction in rat brain[END_REF]. A reduction in cytochrome oxidase activity was also accompanied by significant Al-induced changes in enzyme Arrhenius plot [START_REF] Dua | Effect of aluminium phosphide exposure on kinetic properties of cytochrome oxidase and mitochondrial energy metabolism in rat brain[END_REF]. Complex III activity was found to be significantly inhibited by Al nanoparticles that also induced a sharp decrease in mitochondrial membrane potential and cytochrome c leakage in isolated brain mitochondria (Arab-Nozari et al., 2019). Reduced activity of electron transport chain complexes from Al-treated rats was accompanied by reduction in particular cytochromes cyt a, cyt b, and cyt c, as well as altered mitochondrial ultrastructure in hippocampus and striatum [START_REF] Kumar | Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminium[END_REF]. Complex V (ATP-synthase) was also down-regulated along with other fragments of electron

Mitochondrial dysfunction

U N C O R R E C T E D P R O O F
transport chain upon Al exposure (Sharma et al., 2013a,b). Correspondingly, analysis of mitochondrial ultrastructure in Al-exposed neurons revealed mitochondrial swelling, cavitation, altered inner mitochondrial membrane and cristae structure [START_REF] Niu | Aluminum impairs rat neural cell mitochondria in vitro[END_REF], as well as loss of cristae, chromatin condensation and decreased number of mitochondria (Sharma et al., 2013a,b). The latter is indicative of Al-induced decrease in mitochondrial biogenesis through down-regulation of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and the downstream genes including Nrf1, Nrf2, and mitochondrial transcription factor A (Tfam) (Sharma et al., 2013a,b). Taken together, these Al-induced changes result in alteration of mitochondrial transmembrane potential and impaired oxidative phosphorylation that may contribute to increased generation of reactive oxygen species [START_REF] Iglesias-González | Effects of aluminium on rat brain mitochondria bioenergetics: an in vitro and in vivo study[END_REF]. However, results from another study indicate that oxidative stress precedes mitochondrial dysfunction in brain of Al-exposed gerbils (Vučetić- [START_REF] Arsić | Oxidative stress precedes mitochondrial dysfunction in gerbil brain after aluminum ingestion[END_REF].

Induction of apoptosis in Al-exposed cells represents one of the mechanisms of direct Al-induced cell damage. Specifically, Al was capable of inducing apoptosis in neuronal (SH-SY5Y), glial (U373MG), and retinal epithelial cells (RPE D407) [START_REF] Toimela | Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin[END_REF]. Exposure of co-cultured neurons and astrocytes to Al resulted in significant metal accumulation on both cell lines, whereas Al-induced apoptosis was revealed only in astrocytes [START_REF] Suárez-Fernández | Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death[END_REF]. In agreement, intensified neuronal apoptosis was observed in a number of in vivo studies [START_REF] Çabuş | A histological study of toxic effects of aluminium sulfate on rat hippocampus[END_REF][START_REF] Keshava | AlCl 3 causes Fas/Fas-L mediated cell death in the cortex and hippocampus of mouse brain[END_REF].

As stated earlier, mitochondrial dysfunction causes cytochrome c leakage that binds Apaf-1 with subsequent formation of apoptosome and procaspase 9 activation underlying Al-induced apoptotic neuronal death [START_REF] Savory | Intracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain[END_REF], thus indicative of mitochondrial pathway of apoptosis (Fig. 2). Another study demonstrated that prooxidant effect of AlCl 3 was associated with a significant increase in cerebral levels of caspase-3 and Bax, whereas antiapoptotic Bcl2 was found to be down-regulated by Al treatment [START_REF] Mesole | Apoptotic inducement of neuronal cells by aluminium chloride and the neuroprotective effect of eugenol in wistar rats[END_REF]. Cortical and hippocampal proapoptotic p53, p21, Bax, caspase 3, and pJNK levels were increased in response to oral Al treatment along with a two-to threefold increase in

4. Apoptosis U N C O R R E C T E D P R O O F
Fas levels, being indicative of involvement of Fas/FasL-mediated apoptosis [START_REF] Keshava | AlCl 3 causes Fas/Fas-L mediated cell death in the cortex and hippocampus of mouse brain[END_REF]. The role of Fas/FasL apoptotic pathway has also been confirmed by the observation of Al-induced caspase-8 [START_REF] Qin | Effects of chronic aluminum lactate exposure on neuronal apoptosis and hippocampal synaptic plasticity in rats[END_REF] and DAXX up-regulation (Kumar et al., 2009a,b;[START_REF] Lukiw | Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture[END_REF], which is known to be p53-independent [START_REF] Wasylishen | Daxx functions are p53-Independent in vivo[END_REF]. Taken together with the earlier demonstrated increase in p53-associated proapoptotic signaling under Al exposure [START_REF] Johnson | Aluminum-maltolate induces apoptosis and necrosis in neuro-2a cells: potential role for p53 signaling[END_REF], these findings indicate that Al-induced apoptosis may involve both p53-dependent and -independent pathways. The use of necrostatin 1 and Z-VAD-FMK, a pan-caspase inhibitor, demonstrated that Al-induced neuronal cell death may involve activation of both necrosis and apoptosis (Hao et al., 2019). This observation corresponds to the proposed role of necroptosis in Al neurotoxicity (Zhang, 2018a,b). The latter was observed at high doses (450 mg/ kg AlCl 3 ), whereas lower doses more likely induced apoptosis through IL-1β/JNK signaling pathway [START_REF] Zhang | Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway[END_REF]. Another study also demonstrated that Al-induced apoptosis and necrosis differentially involved ERK and p38 MAPK/ERK signaling pathways in SH-SY5Y cells, respectively [START_REF] Jia | MAPK signaling pathways involved in aluminum-induced apoptosis and necroptosis in SH-SY5Y cells[END_REF].

As Al is capable of inducing apoptosis in brain cells, it clearly modulates cell cycle in brain cells. A recent study by [START_REF] Reichert | Aluminum affects neural phenotype determination of embryonic neural progenitor cells[END_REF] demonstrated that Al 3 + inhibited proliferation of neural progenitor cells during neural differentiation and induced apoptosis along with modulation of cell cycle by increasing sub-G1 phase and reducing G2/M phase [START_REF] Reichert | Aluminum affects neural phenotype determination of embryonic neural progenitor cells[END_REF]. At the same time, in cultured astrocytes Al-induced apoptosis was associated with a shift from S phase to G2/M phase (Guo and Liang, 2001). Al exposure also increases neuronal expression of cyclin-dependent kinase 5 (Cdk5) [START_REF] Bihaqi | Neuroprotective role of Convolvulus pluricaulis on aluminium induced neurotoxicity in rat brain[END_REF], playing an essential role in regulation of neuronal differentiation [START_REF] Cicero | Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation[END_REF]. Several studies demonstrated that a significant increase in cyclin D1 expression in Al-exposed rat brains (Kumar et al., 2009a,b). In contrast, exposure of PC12 cells to Al nanoparticle significantly increased p21 and decreased cyclin D1 expression ultimately resulting in G1 cell cycle arrest [START_REF] Liu | Neurotoxicity of aluminum oxide nanoparticles and their mechanistic role in dopaminergic neuron injury involving p53-related pathways[END_REF].

Existing data demonstrate proinflammatory effects of Al [START_REF] Lukiw | Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture[END_REF]. Specifically, Al exposure was shown to increase expression of proinflammatory cytokines IL-1b, IL-6, TNF-a, and MIP-1a whereas

Neuroinflammation and microglial activation

U N C O R R E C T E D P R O O F
expression of brain derived neurotrophic factor (BDNF) was significantly reduced [START_REF] Cao | Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat[END_REF][START_REF] Kasbe | Mangiferin ameliorates aluminium chloride-induced cognitive dysfunction via alleviation of hippocampal oxido-nitrosative stress, proinflammatory cytokines and acetylcholinesterase level[END_REF][START_REF] Prema | Fenugreek seed powder attenuated aluminum chloride-induced tau pathology, oxidative stress, and inflammation in a rat model of Alzheimer's disease[END_REF]. Increased expression of proinflammatory cytokines may be associated with up-regulation of nuclear factor-kappa beta (NF-κB) expression [START_REF] Sood | Stress proteins and glial cell functions during chronic aluminium exposures: protective role of curcumin[END_REF][START_REF] Zhao | Neuroprotective effects of Syringic acid against aluminium chloride induced oxidative stress mediated neuroinflammation in rat model of Alzheimer's disease[END_REF], being the key regulator of inflammation [START_REF] Shih | NF-kappaB signaling pathways in neurological inflammation: a mini review[END_REF]. Particularly, a significant down-regulation of NF-κB inhibitor gene was observed in brains of mice subcutaneously exposed to Al [START_REF] Li | Subcutaneous injections of aluminum at vaccine adjuvant levels activate innate immune genes in mouse brain that are homologous with biomarkers of autism[END_REF]. It is also notable that co-exposure of Al and mercury (as sulfates) significantly potentiated neurotoxic effect of each of these metals alone via NF-κB induction and subsequent proinflammatory signaling, as noted in human neuronal and glial cells co-culture (Alexandrov et al., 2018). Therefore, NF-κB may be considered as a link between Al-induced neuroinflammation and amyloidogenesis (Alawdi et al., 2017). Together with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a dopaminergic neurotoxicant, Al exposure is capable of inducing hippocampal expression of AP-1 [START_REF] Li | Chronic exposure to low levels of aluminum alters cerebral cell signaling in response to acute MPTP administration[END_REF], another redox sensitive transcription factor involved in regulation of inflammatory response.

Proinflammatory effect of Al hydroxide was shown to be associated with inflammasome activation and subsequent IL-1β secretion by microglia (Gustin et al., 2015). The results obtained in another study demonstrated that apurinic/apyrimidinic endonuclease 1 may be also considered as negative regulator of Al neuroinflammation [START_REF] Zaky | Apurinic/ apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation[END_REF]. It is also notable that induction of systemic inflammation characterized by elevated proinflammatory cytokine (IL-6, TNF-a) and mi-croRNA (miRNA-9, miRNA-125b and miRNA-146a) levels may also contribute to Al-induced inflammatory neurodegeneration [START_REF] Pogue | Systemic inflammation in C57BL/ 6J mice receiving dietary aluminum sulfate; up-regulation of the pro-inflammatory cytokines IL-6 and TNFα, C-reactive protein (CRP) and miRNA-146a in blood serum[END_REF] U In addition to overproduction of proinflammatory cytokines, Al exposure was also shown to increase both COX-1 and COX-2 activity in cortex and/or hippocampus [START_REF] Syed | Cyclooxygenase I and II inhibitors distinctly enhance hippocampal-and cortex-dependent cognitive functions in mice[END_REF]. In agreement, Al-induced COX-downstream signaling involving increased prostaglandin synthase and receptor expression, as well as prostaglandin levels in hippocampus [START_REF] Wang | Hippocampal neuronal cyclooxygenase-2 downstream signaling imbalance in a rat model of chronic aluminium gluconate administration[END_REF]. It is also notable that the use of synthetic prostaglandin E1 (PGE1) analogue, misoprostol, ameliorated Al-induced memory and learning dysfunction through modulation of PGES-PGE2-EP signaling pathway and decreasing PGE2, mPGES-1, EP2, and EP4 expression (Guo et al., 2016). AlCl 3 -exposed mice treated with COX inhibitor ibuprofen also demonstrated that Al toxicity is associated with hippocampal overexpression of neuronal pentraxin 1 (NP1) (Jamil et al.,

N C O R R E C T E D P R O O F
U N C O R R E C T E D P R O O F 2016)
that is considered one of the key factors of Aβ-induced neurite loss and synaptic dysfunction [START_REF] Abad | Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-β and is overexpressed in dystrophic neurites in Alzheimer's brain[END_REF].

Al -induced (micro)gliosis is considered as the key component of neuroinflammation [START_REF] Blaylock | Aluminum induced immunoexcitotoxicity in neurodevelopmental and neurodegenerative disorders[END_REF]. Particularly, exposure to Al was shown to induce oxidative stress-dependent glial activation in rat brain (Akinrinade et al., 2015a,b), being especially observed in striatum and thalamus [START_REF] Platt | Aluminium toxicity in the rat brain: histochemical and immunocytochemical evidence[END_REF]. Nanoscaled silica was also shown to induce glial activation in rat brain cortex and hippocampus as assessed by increased number of ED1, GFAP, and nestin-positive cells [START_REF] Li | Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains[END_REF]. Moreover, [START_REF] Campbell | Pro-inflammatory effects of aluminum in human glioblastoma cells[END_REF] demonstrated that Al sulfate was shown to increase proliferation of glioblastoma cells with the effect comparable to that for LPS [START_REF] Campbell | Pro-inflammatory effects of aluminum in human glioblastoma cells[END_REF]. It was also demonstrated that glial cells accumulate significantly more Al and iron, although being less sensitive to metal-induced oxidative stress when compared to neurons [START_REF] Oshiro | Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells[END_REF]. These findings also correspond to a recent observation of increased Al deposition in microglia, as well as other inflammatory cells in a patient with cerebral amyloid angiopathy [START_REF] Mold | Intracellular aluminium in inflammatory and glial cells in cerebral amyloid angiopathy: a case report[END_REF].

It has been demonstrated that Al glycinate exposure down-regulates mRNA expression of molecular chaperone BiP/Grp78, as well as certain Ca-handling proteins (e.g., calnexin, calreticulin, stanniocalcin 2), thus inhibiting adaptive response and predisposing astrocytes to ERS (Aremu et al., 2011). Al-induced ERS characterized by an increase in CHOP and caspase 12 expression was shown to induce p53-independent cell death in SH-SY5Y neuroblastoma cells along with development of oxidative stress and Aβ1-40 accumulation [START_REF] Rizvi | Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53[END_REF]. Similarly, development of ERS characterized by increased GADD153 translocation was accompanied by NF-κB induction and Bcl-2 down-regulation (Ghribi et al., 2001). A later study also demonstrated up-regulation of ERS pathway-associated proteins including PERK, EIF2α, and CHOP as a component of Al-induced neurotoxic effect [START_REF] Bharathi | Amelioration of aluminum maltolate-induced inflammation and endoplasmic reticulum stress-mediated apoptosis by tannoid principles of emblica officinalis in neuronal cellular model[END_REF]. It is proposed that Al-dependent induction of PERK-EIF2α signaling with subsequent unfolded protein response may induce inflammation in human neuroblastoma SH-SY5Y cells [START_REF] Rizvi | Aluminum activates PERK-eIF2α signaling and inflammatory proteins in human neuroblastoma SH-SY5Y cells[END_REF].

Endoplasmic reticulum stress (ERS) and altered

Ca 2 + homeostasis U N C O R R E C T E D P R O O F
Given the role of ER in Ca2 + handling, altered intracellular Ca levels may be also indicative of ER dysfunction [START_REF] Rizvi | Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53[END_REF]. The role of altered Ca2 + homeostasis as the mechanism of Al neurotoxicity was proposed by [START_REF] Julka | Altered calcium homeostasis: a possible mechanism of aluminium-induced neurotoxicity[END_REF]. Chronic Al exposure was shown to increase synaptosomal Ca levels through reduction of Ca2 +-ATPase activity [START_REF] Kaur | Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats[END_REF]. Taken together with increased Ca2 + release from mitochondria these changes result in increased intracellular Ca2 + levels (Gandolfi et al., 1998). In addition, Al-Aβ conjugate was shown to affect neuronal Ca2 + homeostasis [START_REF] Drago | Aluminum modulates effects of β Amyloid1-42 on neuronal calcium homeostasis and mitochondria functioning and is altered in a triple transgenic mouse model of Alzheimer's disease[END_REF]. Microarray analysis of 35,129 genes in Al-exposed SH-SY5Y cells demonstrated that alteration of Ca2 + homeostasis is the key mechanism mediating neuronal and/or synaptic dysfunction (Gatta et al., 2011). Thus, due to its role in increasing intracellular Ca2 + concentrations, Al can be considered excitotoxic [START_REF] Exley | Human exposure to aluminium[END_REF].

Impairment of synaptic plasticity and transmission is known to underlie multiple adverse neurological effects of Al (Zhang, 2018a,b) affecting both presynaptic and postsynaptic mechanisms [START_REF] Chen | Early chronic aluminium exposure impairs long-term potentiation and depression to the rat dentate gyrus in vivo[END_REF]. Correspondingly, laboratory studies demonstrated a significant negative effect of Al on synaptic plasticity (Wang et al., 2002), being strongly dependent on the ontogenetic period with the most prominent effect observed in adulthood (Wang et al., 2002b). Al exposure resulted in a significant decrease of field excitatory postsynaptic potentials after high-frequency stimulation, being indicative of synaptic dysfunction [START_REF] Qin | Effects of chronic aluminum lactate exposure on neuronal apoptosis and hippocampal synaptic plasticity in rats[END_REF]. Al-induced alteration of synapse ultrastructure are characterized by decreased postsynaptic density thickness, increased synaptic cleft width, high frequency of flat synapses, and reduced number of perforated synapse [START_REF] Jing | Quantitative study of aluminum-induced changes in synaptic ultrastructure in rats[END_REF]. Increased rigidity of synaptosomes under Al exposure due to redox-dependent modulation of membrane fluidity and membrane lipid composition (Ahmed et al., 2020a) may reduce the release of synaptic vesicles into synaptic cleft (Ahmed et al., 2020b). Al was also shown to inhibit synaptic (Na +/ K +)ATPase activity and contributing to synaptic dysfunction [START_REF] Silva | The inhibitory effect of aluminium on the (Na +/K +) ATPase activity of rat brain cortex synaptosomes[END_REF]. Al-maltol exposure resulted in a significant alteration of synaptic structure characterized by decreased number of axon 7. Reduced synaptic plasticity and neurotrophin production

U N C O R R E C T E D P R O O F
branches and dendritic spines along with neuronal atrophy, being associated with mGluR up-regulation and down-regulation of PKC and the NM-DAR subunits (Pan et al., 2020a,b). Another study proposed Al-induced modulation of the PI3K-Akt-mTOR pathway, could result in alterations in synaptic plasticity (Li et al., 2020a,b).

Adverse effects of Al exposure on synaptic plasticity and neurite growth may be mediated by negative regulation of neurotrophic factor production. Al-maltol induced a significant decrease in nerve growth factor (NGF) and BDNF expression in brain cell cultures [START_REF] Johnson | Aluminum disrupts the pro-inflammatory cytokine/ neurotrophin balance in primary brain rotation-mediated aggregate cultures: possible role in neurodegeneration[END_REF]. The decrease in synaptic long-term potentiation in Al-exposed rats was associated with a significant reduction of BDNF expression through modulation of Histone H3K9 demethylation (H3K9me2) demethylase and plant homeodomain finger protein 8 (PHF8) (Li et al., 2020a,b). Other epigenetic mechanisms involving H3K4me3, H3K27me3 and H3K9me2 may also underlie altered BDNF and early growth response protein 1(EGR1) under occupational Al exposure (Pan et al., 2020a,b). Correspondingly, hippocampal expression of activity-regulated cytoskeleton-associated protein (ARC) gene, known to play a significant role in synaptic plasticity [START_REF] Korb | Arc in synaptic plasticity: from gene to behavior[END_REF], was also found to be reduced following in utero Al exposure [START_REF] Inohana | Developmental exposure to aluminum chloride irreversibly affects postnatal hippocampal neurogenesis involving multiple functions in mice[END_REF]. The underlying mechanism was shown to involve a decrease in BDNF-induced Arc expression through alteration of ERK signaling [START_REF] Chen | Nonlethal aluminum maltolate can reduce brain-derived neurotrophic factor-induced Arc expression through interrupting the ERK signaling in SH-SY5Y neuroblastoma cells[END_REF]. Other mechanisms involved in altered synaptic plasticity upon Al exposure may include deregulation of SIRT1, TORC1 and pCREB levels [START_REF] Yan | Effects of aluminium on long-term memory in rats and on SIRT 1 mediating the transcription of CREB-dependent gene in hippocampus[END_REF] and cAMP-PKA-CREB pathway [START_REF] Zhang | Aluminium chloride impairs long-term memory and downregulates cAMP-PKA-CREB signalling in rats[END_REF].

Cytoskeleton and microtubules in particular were considered as the potential targets for Al toxicity [START_REF] Walton | Chronic aluminum intake causes Alzheimer's disease: applying Sir Austin Bradford Hill's causality criteria[END_REF], resulting in altered axonal transport and perikaryal aggregation [START_REF] Kushkuley | Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms[END_REF]. Particularly, Al exposure resulted in a significant aggregation and disruption of cytoskeletal proteins in cerebral cortex, corpus striatum and hippocampus [START_REF] Kaur | Neurofilament phosphorylation and disruption: a possible mechanism of chronic aluminium toxicity in Wistar rats[END_REF]. After prolonged exposure Al -rich pyramidal cells are characterized by microtubule depletion with neurite damage and loss of synapse density [START_REF] Walton | Brain lesions comprised of aluminum-rich cells that lack microtubules may be associated with the cognitive deficit of Alzheimer's disease[END_REF]. Particularly, Al is capable of inhibiting neurofilament assembly to axonal cytoskeleton, translo

Cytoskeletal pathology

Molecular mechanisms of aluminum neurotoxicity

U N C O R R E C T E D P R O O F
cation and degradation of neurofilaments in axonal neurites [START_REF] Shea | Aluminum inhibits neurofilament assembly, cytoskeletal incorporation, and axonal transport[END_REF]. Generally, these observations corroborate earlier data on sharp reduction in neurofilament and tubulin genes in spinal cord motor neurons [START_REF] Muma | Aluminum neurotoxicity: altered expression of cytoskeletal genes[END_REF] contributing to neuro-fibrillary degeneration [START_REF] Katsetos | Neuronal cytoskeletal lesions induced in the CNS by intraventricular and intravenous aluminium maltol in rabbits[END_REF]. A recent study demonstrated that Al(III) affects microtubule assembly far more effectively than iron [START_REF] Shevtsov | Effect of aluminum, iron, and zinc ions on the assembly of microtubules from brain microtubule proteins[END_REF]. Al-induced alterations in cytoskeleton may also involve modulatory effects on amyloid β and α-synuclein accumulation.

Amyloid β

Modulation of amyloid generation and accumulation is considered as the potential pathway of Al-induced neurodegeneration in Alzheimer's disease (Exley, 2005)(Fig. 3). Generally, this suggestion is based on the observation of cooccurrence between Al and amyloid deposits in neurodegenerative diseases [START_REF] Mirza | Aluminium in brain tissue in familial Alzheimer's disease[END_REF][START_REF] Mold | Intracellular aluminium in inflammatory and glial cells in cerebral amyloid angiopathy: a case report[END_REF].

Al-maltolate exposure was shown to increase Aβ1-42 expression in rat brain through up-regulation of APP, β-(BACE1), and γ-secretase (presenilin-1) mRNA transcription and protein expression in rat brain regions [START_REF] Liang | Impact of sub-chronic aluminium-maltolate exposure on catabolism of amyloid precursor protein in rats[END_REF][START_REF] Thenmozhi | Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer's disease in Wistar rats[END_REF]. These changes are also associated with a significant decrease of α-secretase proteins (ADAM9, ADAM10, ADAM17) [START_REF] Wang | Effects of aluminium on β-amyloid (1-42) and secretases (APP-cleaving enzymes) in rat brain[END_REF]. In vitro studies in cell lines also demonstrate a significant impact of Al on proteins of amyloidogenic pathway. Al exposure was shown to increase BACE1 (LI) and BACE2 levels [START_REF] Castorina | Early effects of aluminum chloride on beta-secretase mRNA expression in a neuronal model of ß-amyloid toxicity[END_REF], although a significant decrease in both enzyme expression could be observed at long-term exposure [START_REF] Castorina | Early effects of aluminum chloride on beta-secretase mRNA expression in a neuronal model of ß-amyloid toxicity[END_REF]. Certain studies also demonstrate that along with increasing Aβ production, Al exposure may negatively affect its degradation by decreasing neprilysin expression [START_REF] Luo | Altered expression of Aβ metabolism-associated molecules from d-galactose/AlCl3 induced mouse brain[END_REF]. Inhibition of plasmin cascade by Al [START_REF] Korchazhkina | The degradation of Aβ 25-35 by the serine protease plasmin is inhibited by aluminium[END_REF]) may be also responsible for both APP α-cleavage and Aβ degradation [START_REF] Zhao | Evoking plasmin for β-amyloid clearance[END_REF]. Al is also capable of inhibiting microglial phagocytosis of Aβ42 peptides [START_REF] Zhao | Aluminum-induced amyloidogenesis and impairment in the clearance of amyloid peptides from the central nervous system in Alzheimer's disease[END_REF] due to TREM2 down-regulation (Alexandrov et al., 2013).

Promotion of amyloid β oligomerization under Al exposure may also play a crucial role in Al-associated Alzheimer's disease. Pioneer studies by Exley et al. (1993) and [START_REF] Kawahara | Aluminum promotes the aggregation of Alzheimer′ s Amyloid β-Protein in vitro[END_REF] demonstrated direct interaction between Al and amyloid β with increasing aggregation of the latter. Later studies have unraveled the particular features of Al-amyloid

U N C O R R E C T E D P R O O F
β interaction and its effects on the protein structure [START_REF] Narayan | Does aluminium bind to histidine? An NMR investigation of amyloid β12 and amyloid β16 fragments[END_REF][START_REF] Turner | Molecular dynamics simulation of aluminium binding to amyloid-β and its effect on peptide structure[END_REF]. Particularly, Al(III) is capable of inducing β-sheet formation and subsequent aggregation of Aβ40 (Zhang et al., 2019). Similar effect was observed for Aβ42 with Al(III) and Fe(II)/ Fe(III) being more active promoters of Aβ42 aggregation than Cu(II) and Zn(II) [START_REF] House | Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ 42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease[END_REF].

In addition to modulation of Aβ production and aggregation, Al was also shown to be involved in induction of tau hyperphosphorylation [START_REF] El-Sebae | Aluminum interaction with human brain tau protein phosphorylation by various kinases[END_REF]. Correspondingly, D-galactose and Al chloride treatment were shown to increase phosphorylated tau deposition in brain regions [START_REF] Chiroma | D-galactose and aluminium chloride induced rat model with cognitive impairments[END_REF]. Al oxide nanoparticles directly interact with the hydrophilic residues of tau protein resulting in cytotoxicity in in SH-SY5Y cells [START_REF] Kermani | Aluminium oxide nanoparticles induce structural changes in tau and cytotoxicity of the neuroblastoma cell line[END_REF]. Neurotoxic effect of Al and D-galactose were also shown to be dependent on GSK-3β activity [START_REF] Chiroma | Centella asiatica protects d-galactose/AlCl3 mediated Alzheimer's disease-like rats via PP2A/GSK-3β signaling pathway in their Hippocampus[END_REF], that is known to play a significant role in tau hyperphosphorylation in AD and cerebral ischemia [START_REF] Culbreth | GSK-3β, a double-edged sword in Nrf2 regulation: implications for neurological dysfunction and disease[END_REF]. In turn, reducing GSK-3β activity may be involved in decreasing Aβ production and tau phosphorylation in Al-exposed PC12 cells [START_REF] Huang | Hyperforin attenuates aluminum-induced Aβ production and Tau phosphorylation via regulating Akt/ GSK-3β signaling pathway in PC12 cells[END_REF].

However, certain negative findings indicate a lack of Al(III) impact on amyloid β and tau accumulation in AβPP and AβPP/tau transgenic mice (Akiyama et al., 2012). Although being somewhat contradictory to other studies, these observations may be indicative of complex mechanisms of Al neurotoxicity involving a wide variety of mechanisms.

α-Synuclein

The earlier demonstrated association between Al exposure and PD may be at least partially mediated by the interplay between Al(III) and α-synuclein. Particularly, Al treatment was shown to increase α-synuclein fibril formation more effectively than Cu(II), Fe(III), Co(III), and Mn(III) [START_REF] Uversky | Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein a possible molecular link between parkinson′ s disease and heavy metal exposure[END_REF]. Correspondingly, knockdown of α-synuclein expression in PC12 cells was shown to ameliorate Al-maltolate toxicity, being indicative of the essential role of α-synuclein in Al neurotoxicity [START_REF] Saberzadeh | Alpha synuclein protein is involved in Aluminum-induced cell death and oxidative stress in PC12 cells[END_REF]. In addition, Al(III) was shown to possess synergistic effect on tau oligomer formation with GSK-3β, as well as to promote tau coaggregation with α-synuclein [START_REF] Nübling | Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level[END_REF].

U N C O R R E C T E D P R O O F

Adverse neurological effects of Al exposure are at least partially mediated by interference of Al with neurotransmitter metabolism and signal transduction. Although the particular mechanisms are still unknown, the existing data clearly demonstrate that Al exposure has a significant impact on glutamatergic, gabaergic, cholinergic, serotoninergic and dopaminergic neurotransmission (Gonçalves and Silva, 2007).

Glutamatergic-gabaergic systems

The majority of the existing studies were devoted to investigation of the impact of Al on glutamatergic mechanisms. Al exposure was shown to reduce NMDA, AMPA, and glutamate-mediated currents in hippocampal neurons [START_REF] Platt | Aluminium reduces glutamate-activated currents of rat hippocampal neurones[END_REF]. Al exposure was shown to reduce hippocampal expression of AMPA receptor subunits GluR-1 and GluR-2 [START_REF] Liu | Role of NMDA receptor in damage of learning and memory induced by sub-chronic aluminum exposure[END_REF] that may be at least partially mediated by modulation of Akt/GSK-3β Pathway (Zhang et al., 2016a,b,c). A dose-dependent hippocampal NMDA receptor (NMDAR) expression was observed in orally exposed rats [START_REF] Jin | Effect of aluminum on Ca 2 + concentration and expression of phospholipase C and NMDA receptor α genes in hippocampus of weaning rats as well as their neural behavior through subchronic exposure[END_REF] with NMDAR 1A and NMDAR 2A/B subunits affected [START_REF] Yuan | Aluminum alters NMDA receptor 1A and 2A/ B expression on neonatal hippocampal neurons in rats[END_REF]. Altered NMDAR expression was also associated with reduced PLC expression [START_REF] Jin | Effect of aluminum on Ca 2 + concentration and expression of phospholipase C and NMDA receptor α genes in hippocampus of weaning rats as well as their neural behavior through subchronic exposure[END_REF]. Al was also shown to aggravate diabetes-associated alteration of neuroblast differentiation and NMDAR signaling [START_REF] Nam | Effects of long-term exposure to aluminum in the hippocampus in the type 2 diabetes model rats[END_REF]. At the same time, the use of NMDAR antagonist partially reversed adverse effects of Al in primary neural cultures, indicative of excitotoxic component in Al toxicity (Atterwill et al., 1996). It is also proposed that Al exposure may alter ability of astrocytes to protect neurons from excitotoxic effect of high glutamate levels [START_REF] Sass | Aluminum pretreatment impairs the ability of astrocytes to protect neurons from glutamate mediated toxicity[END_REF].

Al also induced an increase in hippocampal and cortical glutamine levels through increase in glutamine-synthetase [START_REF] Struys-Ponsar | Effects of Aluminum on Glutamate Metabolism[END_REF] and reduced glutaminase activity in astrocytes [START_REF] Zielke | A glutamatergic mechanism for aluminum toxicity in astrocytes[END_REF], whereas glutamate accumulation was reduced [START_REF] Struys-Ponsar | Effects of aluminum exposure on glutamate metabolism: a possible explanation for its toxicity[END_REF]. Metabolomic study involving HT-29 cells also revealed a significant Al-induced decrease in intracellular glutamate levels (Yu et al., 2019a,b). In agreement, down-regulation of glutamate-NO-cGMP pathway in neurons under Al treatment was observed both in vitro and in vivo [START_REF] Canales | Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology[END_REF].

Altered neurotransmitter metabolism

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At the same time, i.p. Al administration resulted in a significant increase in glutamate levels in thalamus, hippocampus, and cerebellum along with elevation of glutamate alpha-decarboxylase activity, whereas GABA transaminase was found to be reduced [START_REF] Nayak | Effects of aluminium exposure on brain glutamate and GABA systems: an experimental study in rats[END_REF]. Aluminum was shown to have a biphasic effect on GABA-evoked currents by potentiation observed at lower levels (< 100 μM) and reduction at higher concentration (≥ 300 μM) [START_REF] Trombley | Selective modulation of GABAA receptors by aluminumJ[END_REF]. Modulatory effect of Al on GABA transport may be mediated through Ca2 +/ calmodulin/calcineurin pathway [START_REF] Cordeiro | Aluminium-induced impairment of Ca2 + modulatory action on GABA transport in brain cortex nerve terminals[END_REF].

Cholinergic system

Cholinergic system was shown to be highly vulnerable in response to Al exposure [START_REF] Yellamma | Cholinergic system under aluminium toxicity in rat brain[END_REF]. Al exposure was shown to reduce cerebral acetylcholinesterase (AChE) activity (Sharma et al., 2013a,b) with a biphasic response characterized by an increase in enzyme activity at shorter periods of exposure following by a subsequent depression [START_REF] Kumar | Biphasic effect of aluminium on cholinergic enzyme of rat brain[END_REF]. Perinatal Al exposure resulted in a significant decrease in cerebellar AChE activity in the offspring (Ghorbel et al., 2016). Expression of choline acetyltransferase and the subsequent acetylcholine synthesis was also found to be reduced in response to Al exposure even despite substrate availability (Farhat et al., 2017). At the same time, certain studies revealed an Al-induced increase in brain AChE activity [START_REF] Khan | Impact of caffeic acid on aluminium chloride-induced dementia in rats[END_REF]. Applying whole-cell patch clamp technique to isolated rat trigeminal ganglion neurons, [START_REF] Hu | Potentiation of the nicotinic acetylcholine receptor by aluminum in mammalian neurons[END_REF] observed that Al 3 + potentiated nicotine-evoked inward currents in a concentration-dependent manner. The authors concluded that the enhanced function of nAChR induced by Al might underlie the neurological alteration induced by Al [START_REF] Hu | Potentiation of the nicotinic acetylcholine receptor by aluminum in mammalian neurons[END_REF].

Moreover, Al exposure is also known to be associated with reduced binding activity of M1 muscarinic acetylcholine receptors (M1AChR) [START_REF] Harkany | Chronic aluminum treatment results in aluminum deposits and affects Ml muscarinic receptors in rat brain[END_REF] as well as nicotinic acetylcholine receptor (α7, α4 and β2 nAChR) gene expression (Farhat et al., 2019). Importantly, this reduction in nicotinic receptor gene expression is associated with severen neurodegeneration and impaired hippocampus dependent learning in mice (Farhat et al., 2019).

Cholinergic dysfunction may also occur from Al-dependent oxidative stress-induced increase in choline synaptic uptake (Amador et al., 2001). Correspondingly, the use of NOS inhibitors demonstrated that al

U N C O R R E C T E D P R O O F
tered cholinergic neurotransmission under Al exposure may be at least partially mediated by disturbances in NO generation [START_REF] Stevanović | Nitric oxide synthase inhibitors protect cholinergic neurons against AlCl3 excitotoxicity in the rat brain[END_REF].

Dopaminergic system

Dopaminergic neurotransmission was found to be significantly inhibited by Al exposure [START_REF] Laabbar | Curcumin prevents the midbrain dopaminergic innervations and locomotor performance deficiencies resulting from chronic aluminum exposure in rat[END_REF]. Correspondingly, cerebral dopamine levels were found to be significantly reduced in Al-exposed animals (Bhalla et al., 2010a,b;[START_REF] Singla | Zinc improves cognitive and neuronal dysfunction during aluminium-induced neurodegeneration[END_REF]. Dopamine synthesis in striatal synaptosomes was also found to be reduced under Al exposure [START_REF] Pavandi | Effect of aluminium and copper on dopamine synthesis in striatal synaptosomes of Rat's brain[END_REF]. In addition, Al reduced dopamine D1-like and D2-like receptor expression predominantly in brain cortex and rostral striatum [START_REF] Kim | Aluminum exposure decreases dopamine D1 and D2 receptor expression in mouse brain[END_REF]. Despite these interactions of Al with the dopaminergic system, results of a 36-year multicenter study suggest that aluminum's main toxicity is associated with Alzheimer's disease, Down's syndrome and dialysis dementia syndrome, but not Parkinson's disease or other neurological disorders [START_REF] Lukiw | Aluminum in neurological disease-a 36 year multicenter study[END_REF]

Serotoninergic system

Certain studies demonstrated that Al exposure may differentially affect serotonin levels [START_REF] Kumar | Aluminium-induced changes in the rat brain serotonin system[END_REF][START_REF] Ravi | Long-term effects of postnatal aluminium exposure on acetylcholinesterase activity and biogenic amine neurotransmitters in rat brain[END_REF][START_REF] Said | Neuroprotective effects of eugenol against aluminiuminduced toxicity in the rat brain[END_REF] and 5-HT2C receptor reactivity [START_REF] Brus | Effect of aluminium exposure on central serotonine and muscarine receptors reactivity in rats[END_REF] in brain regions. Exposure to Al was also shown to reduce circulating serotonin levels (Zhang et al., 2016a,b,c). Interestingly, however, a recent study concludes that Al-induced depressive-like behavior in rats is due to activation of hippocampal IL-1β/JNK signaling pathway, resulting in neuronal death in this region [START_REF] Zhang | Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway[END_REF].

Due to the revealed high potential of Al as neurotoxic agent as well as its role in development of neurodegenerative and neurodevelopmental disorders, multiple studies aimed at investigation of the potential protective strategies. Due to the role of oxidative stress, mitochondrial dysfunction, inflammation, apoptosis and endoplasmic reticulum stress in Al neurotoxicity, the majority of protective substances are expected to mediate their effect through antioxidant and anti-inflammatory activity. How 10. Treatment strategies

U N C O R R E C T E D P R O O F
ever, other more specific mechanisms may also mediate neuroprotective effects. The existing protective agents may be mechanistically divided into the following groups: (i) chelators; (ii) trace elements; (iii) amino acids; (iv) polyphenols; (v) polyphenol-rich phytoextracts; (vi) drugs and other agents.

Chelation therapy

Chelation therapy in treatment of Al toxicity aims to reduce metal bioavailability and facilitates its excretion from the organism, thus preventing its toxic effects. The majority of prior studies demonstrate effective chelation of Al using iron chelator desferrioxamine or deferoxamine (DFO) [START_REF] Kumar | Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review[END_REF]. Particularly, DFO was shown to prevent Al-induced oxidative damage to brain proteins [START_REF] Sivakumar | Aluminium induced structural, metabolic alterations and protective effects of desferrioxamine in the brain tissue of mice: an FTIR study[END_REF]. Ethylene diamine tetraacetic acid (EDTA) (Fulgenzi et al., 2015) and N(2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA) [START_REF] Shrivastava | Combined effect of HEDTA and selenium against aluminum induced oxidative stress in rat brain[END_REF] were also shown to be effective in reducing Al neurotoxicity. At the same time, comparative analysis of efficiency of other existing Al-chelating agents [START_REF] Crisponi | Chelating agents for human diseases related to aluminium overload[END_REF] in treatment of Al neurotoxicity is highly required.

Essential trace elements

The existing data demonstrate that silicon (Si), selenium (Se), and zinc (Zn) may possess neuroprotective effect against Al toxicity.

Epidemiological studies demonstrated that increased silicon intake may prevent adverse neurological effects of Al [START_REF] Davenward | Silicon-rich mineral water as a non-invasive test of the 'aluminum hypothesis' in Alzheimer's disease[END_REF][START_REF] Nielsen | Update on the possible nutritional importance of silicon[END_REF] through its direct interaction with Al ion forming aluminosilicate thus reducing Al bioavailability and toxicity [START_REF] Domingo | Oral silicon supplementation: an effective therapy for preventing oral aluminum absorption and retention in mammals[END_REF]. Particularly, increased Si intake was shown to reduce brain Al accumulation in mice (Granero et al., 2004).

Being a structural component of selenoproteins including glutathione peroxidase, protective effects of Se against Al neurotoxicity may be mediated by its antioxidant activity. Particularly, Se treatment significantly reversed Al-induced inhibition of catalase and glutathione reductase activity, as well as reduction of GSH levels. These effects were also accompanied by improved brain morphology, muscle strength, locomotion, and acetylcholinesterase activity [START_REF] Lakshmi | Protective effect of selenium against aluminum chloride-induced Alzheimer's disease: behavioral and biochemical alterations in rats[END_REF]. In addition, neuroprotective effects of Se under Al exposure were shown to involve de

U N C O R R E C T E D P R O O F
creased inflammatory response and improvement of NO signaling [START_REF] Cao | High Selenium Yeast mitigates aluminum-induced cerebral inflammation by increasing oxidative stress and blocking NO production[END_REF].

Zinc was shown to ameliorate adverse effects of Al exposure on brain morphology and redox status, dopamine and serotonin levels, as well as acetylcholinesterase activity [START_REF] Lu | Optimal dose of zinc supplementation for preventing aluminum-induced neurotoxicity in rats[END_REF]. Particularly, zinc significantly increased total and reduced glutathione levels, as well as improved activity of antioxidant enzymes and metallothionein levels along with reversal of Al-induced neurodegeneration [START_REF] Singla | Zinc modulates aluminium-induced oxidative stress and cellular injury in rat brain[END_REF]. Improved redox status was also associated with lower expression of redox-sensitive transcription factor NF-κB [START_REF] Singla | Zinc, a neuroprotective agent against aluminum-induced oxidative DNA injury[END_REF]. The authors also demonstrated antiapoptotic effect of Zn in Al-exposed animals through reduction of proapoptotic protein expression including Bax, Apaf-1, caspases 3, 6,7, 8, 9 and improvement of cerebral Bcl2 levels [START_REF] Singla | Zinc down regulates Apaf-1-dependent Bax/Bcl-2 mediated caspases activation during aluminium induced neurotoxicity[END_REF].

Certain other trace elements were shown to be effective against Al neurotoxicity. Specifically, lithium treatment ameliorated adverse effects of Al on brain ultrastructure (Bhalla et al., 2010a), acetylcholinesterase and monoamine oxidase activity, as well as brain dopamine and serotonin levels (Bhalla et al., 2010b). Another study demonstrated preventive effects of boric acid on neuronal ultrastructure under Al exposure [START_REF] Colak | The neuroprotective role of boric acid on aluminum chloride-induced neurotoxicity[END_REF].

Polyphenols

Polyphenols represent a wide group of phytochemicals possessing antioxidant and anti-inflammatory effects thus being used as the potential agents in treatment of Al neurotoxicity. Particularly, quercetin was shown to increase cerebral antioxidant enzyme gene expression (Ali et al., 2014) and improve brain mitochondrial biogenesis and function in Al-exposed animals [START_REF] Sharma | Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway[END_REF]. In parallel with improvement of redox status mangiferin [START_REF] Kasbe | Mangiferin ameliorates aluminium chloride-induced cognitive dysfunction via alleviation of hippocampal oxido-nitrosative stress, proinflammatory cytokines and acetylcholinesterase level[END_REF] and hesperidin [START_REF] Jangra | Hesperidin and silibinin ameliorate aluminum-induced neurotoxicity: modulation of antioxidants and inflammatory cytokines level in mice hippocampus[END_REF] ameliorated Al-induced neuroinflammation, whereas fisetin possessed antiapoptotic effect and reduced Aβ aggregation [START_REF] Prakash | Dietary flavonoid fisetin regulates aluminium chloride-induced neuronal apoptosis in cortex and hippocampus of mice brain[END_REF]. Naringenin (Haider et al., 2020) and curcumin [START_REF] Kakkar | Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain[END_REF] were capable of restoration of acetylcholinesterase activity affected by Al.

Significant neuroprotective effect under Al toxicity was observed for phenolic acids. Particularly, chlorogenic acid was shown to improve redox status and antioxidant enzyme activity through up-regulation of Nrf2-ARE signaling pathway in Al-exposed hippocampal neurons [START_REF] Wang | Effects of chlorogenic acid against aluminium neurotoxicity in ICR mice through chelation and antioxidant actions[END_REF]. Adverse effects of Al treatment on cerebral AChE activity were ameliorated by caffeic [START_REF] Khan | Impact of caffeic acid on aluminium chloride-induced dementia in rats[END_REF] and syringic [START_REF] Zhao | Neuroprotective effects of Syringic acid against aluminium chloride induced oxidative stress mediated neuroinflammation in rat model of Alzheimer's disease[END_REF] acids, whereas the latter also reduced neuroinflammation.

Along with antioxidant and anti-inflammatory effect of the phytochemicals, neuroprotective activity may be at least partially attributed to direct interaction with metal ion. Particularly, it has been demonstrated that polyphenols may bind Al(III) thus reducing its bioavailability (Zhang et al., 2016a,b,c). The role of Al chelation in treatment of neurotoxicity was clearly demonstrated for chlorogenic acid where it increased metal excretion and reduced its accumulation in hippocampus [START_REF] Wang | Effects of chlorogenic acid against aluminium neurotoxicity in ICR mice through chelation and antioxidant actions[END_REF].

Phytochemical-rich plants and phytoextracts

Due to clearly demonstrated protective effect of particular phytochemicals (polyphenols) against Al neurotoxicity, the potential efficiency of polyphenol-rich plant extracts was also investigated. Specifically, neuroprotective, antioxidant, and anti-inflammatory effects were demonstrated for green [START_REF] Jelenković | Influence of the green tea leaf extract on neurotoxicity of aluminium chloride in rats[END_REF] and black tea [START_REF] Mathiyazahan | Protective effect of black tea extract against aluminium chloride-induced Alzheimer's disease in rats: a behavioural, biochemical and molecular approach[END_REF], Allium cepa [START_REF] Singh | Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity[END_REF], grape [START_REF] Lakshmi | Neuroprotective role of hydroalcoholic extract of Vitis vinifera against aluminium-induced oxidative stress in rat brain[END_REF], Ginkgo biloba [START_REF] Verma | Modulatory effects of ginkgo biloba against amyloid aggregation through induction of heat shock proteins in aluminium induced neurotoxicity[END_REF], and saffron [START_REF] Linardaki | Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment[END_REF] to name a few. The growing body of evidence demonstrate the usefulness of ethnobotanical species. However, further studies are required to characterize the particular mechanisms and active agents contributing to neuroprotective effect of phytoextracts under Al exposure.

Other agents

A variety of agents with different mechanism of action were also shown to be effective against Al neurotoxicity including melatonin [START_REF] Sadek | The possible neuroprotective effects of melatonin in aluminum chloride-induced neurotoxicity via antioxidant pathway and Nrf2 signaling apart from metal chelation[END_REF], anti-inflammatory drugs (e.g., ibuprofen) [START_REF] Jamil | Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity[END_REF], lipoic acid (Al-Otaibi et al., 2018), N-acetylcysteine [START_REF] Prakash | Effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage in rats[END_REF], etc. Combined therapy may be also considered as a perspective approach due to the use of agents with different mechanism of biological activity [START_REF] Kumar | Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review[END_REF].

U N C O R R E C T E D P R O O F
The growing body of data demonstrate the potential role of Al exposure and its neurotoxicity as contributors to a wide spectrum of neurodegenerative and neurodevelopmental disorders. The underlying mechanisms of Al(III) neurotoxicity were shown to involve oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, inflammation, cell death, interaction with Aβ and α-synuclein, cytoskeletal abnormalities as well as alteration of synaptic plasticity and signal transduction through interference with neurotransmitter systems. Targeting these mechanisms at different stages may be beneficial for treatment of Al neurotoxicity and associated diseases. However, certain contradictions regarding the mechanisms and the overall effects of Al exposure in vivo and in vitro exist. The latter may at least partially arise from the difference in analytical methodology, whereas development of precise and validated methods including speciation analysis and imaging techniques would significantly contribute to understanding of biological effects of Al. Further studies are required to highlight the intimate mechanisms involved in Al neurotoxicity, as well as its particular contribution to neurological disorders for subsequent development of effective therapeutic strategies. Exley, C., Price, N.C., Kelly, S.M., Birchall, J.D., 1993. An interaction of β-amyloid with aluminium in vitro. FEBS Lett. 324 (3), 293-295. Farhat, S.M., Mahboob, A., Iqbal, G., Ahmed, T., 2017. Aluminum-induced cholinergic deficits in different brain parts and its implications on sociability and cognitive functions in mouse. Biol. Trace Elem. Res. 177 (1), 115-121. Farhat, S.M., Mahboob, A., Ahmed, T., 2019. Oral 3), 315-320. Gatta, V., Drago, D., Fincati, K., Valenti, M.T., Dalle Carbonare, L., Sensi, S.L., Zatta, P., 2011. Microarray analysis on human neuroblastoma cells exposed to aluminum, β 1-42-amyloid or the β 1-42-amyloid aluminum complex. PloS one. 6 (1), e15965. Ghorbel, I., Amara, I.B., Ktari, N., Elwej, A., Boudawara, O., Boudawara, T., Zeghal, N., 2016. Aluminium and acrylamide disrupt cerebellum redox states, cholinergic function and membrane-bound ATPase in adult rats and their offspring. Biol. Trace Elem. Res. 174 (2), 335-346. Ghribi, O., Herman, M.M., DeWitt, D.A., Forbes, M.S., Savory, J., 2001. Aβ (1-42) and aluminum induce stress in the endoplasmic reticulum in rabbit hippocampus, involving nuclear translocation of gadd 153 and NF-κB. Mol. Brain Res. 96 (1-2), 30-38. Gonçalves, P.P., Silva, V.S., 2007. Does neurotransmission impairment accompany aluminium neurotoxicity? J. Inorg. Biochem. 101 (9), 1291-1338. Goullé, J.P., Grangeot-Keros, L., 2020. Aluminum and vaccines: current state of knowledge. Med. Mal. Infect. 50 (1), 16-21. Granero, S., Vicente, M., Aguilar, V., Martínez-Para, M.C., Domingo, J.L., 2004. Effects of beer as a source of dietary silicon on aluminum absorption and retention in mice. Trace Elem. Electroly. 21 (1), 28-32. Guo, G.W., Liang, Y.X., 2001. Aluminum-induced apoptosis in cultured astrocytes and its effect on calcium homeostasis. Brain Res. 888 (2), 221-226. Guo, Y., Lei, W., Wang, J., Hu, X., Wei, Y., Ji, C., Yang, J., 2016. Misoprostol reverse hippocampal neuron cyclooxygenase-2 downstream signaling imbalance in aluminum-overload rats. Curr. Alzheimer Res. 13 (9), 1006-1016. Gustin, A., Kirchmeyer, M., Koncina, E., Felten, P., Losciuto, S., Heurtaux, T., Dostert, C., 2015. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PloS one. 10 (6), e0130624. Haider, S., Liaquat, L., Ahmad, S., Batool, Z., Siddiqui, R.A., Tabassum, S., Naz, N., 2020. Naringenin protects AlCl3/D-galactose induced neurotoxicity in rat model of AD via attenuation of acetylcholinesterase levels and inhibition of oxidative stress. Plos one. 15 (1), e0227631.

Fig. 1

 1 Fig. 1 Mechanisms underlying prooxidant effect of aluminium (Al 3 + ). Al 3 + was shown to affect mitochondrial electron transport chain thus increasing electron leakage from Complex I and III with subsequent formation of superoxide anion radical (O 2 -• ). Another mechanism contributing to superoxide production involves Al-dependent increase in xanthine oxidase (XO) and NADPH-oxidase (NOX) activity. Al 3 + cation is directly involved in the formation of highly reactive Al superoxide semi-reduced radical ion (AlO 2 2 +• ) that was shown to promote prooxidant activity of Fe 2 + in Fenton reaction with generation of hydroxyl radical (HO • ). Prooxidant activity of Al is also aggravated by its inhibitory effect on enzymatic antioxidants including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR). The latter results in reduced glutathione (GSH) depletion. Moreover, Al was shown to down-regulate nuclear factor erythroid 2-related factor 2 (Nrf2), being the key regulator of the antioxidant system. Taken together, these mechanisms result in development of oxidative stress with increased oxidative modification of lipids, proteins and nucleic acids observed in brain/neuronal cell lines under Al exposure.

Fig. 2

 2 Fig. 2 The proposed model of aluminium-induced neuronal apoptosis. Al was shown to induce apoptosis in neuronal cells through distinct pathways. Mitochondrial pathway is directly related to Al-induced mitochondrial dysfunction and subsequent Bax-mediated cytochrome c release. The latter is also stimulated due to positive and negative regulation of p53 and Bcl-2 expression, respectively. Al was shown to increase the rate of cytochrome c binding to Apaf-1 with subsequent formation of apoptosome and caspase 9 activation with subsequent caspase 3 cleavage

Fig. 3

 3 Fig. 3 The role of Al in amyloid β generation. Al exposure promotes amyloidogenic pathway through activation of β-(BACE1) and γ-secretase (presenilin-1), as well as down-regulating non-amyloidogenic pathway due to inhibition of α-secretase. Along with promotion of amyloid oligomerization and aggregation, Al 3 + also inhibits neprilysin and plasmin that are known to be involved in amyloid degradation. In addition, Al exposure was shown to impair TREM2-mediated phagocytosis of amyloid proteins by microglia. Taken together, these effects of Al exposure result in accumulation of amyloid plaques and Alzheimer disease-like neurodegeneration.

  a comparison with Alzheimer's disease, multiple sclerosis and autism. Sci. Rep. 10 (1), 1-7.

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Acknowledgments

The study was performed with the support of the Russian Ministry of Science and Higher Education, Project No. 0856-2020-0008. M.A. was supported in part by grants from the National Institute of Environmental Health Sciences (NIEHS) R01ES07331 and R01ES10563.