Multifaceted effects of aluminium in neurodegenerative diseases: A review

Biomedicine & Pharmacotherapy 83 (2016) 746–754

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Review

Multifaceted effects of aluminium in neurodegenerative diseases: A review S. Maya, T. Prakash* , Krishna Das Madhu, Divakar Goli Department of Pharmacology, Acharya & BM Reddy College of Pharmacy, Bangalore 560 107, Karnataka, India

A R T I C L E I N F O

Article history: Received 13 June 2016 Received in revised form 14 July 2016 Accepted 18 July 2016 Keywords: Aluminium Neurodegeneration Neurotoxicity Amyotrophic lateral sclerosis

A B S T R A C T

Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well-established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases. ã 2016 Elsevier Masson SAS. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aluminium-induced oxidative stress . . . . . . . . . . . . . . . . Aluminium as a cholinotoxic agent . . . . . . . . . . . . . . . . . . Aluminium induced neurotoxicity . . . . . . . . . . . . . . . . . . Aluminium on gene expression . . . . . . . . . . . . . . . . . . . . . Effect of aluminium on cell mediated excitotoxicity . . . . Effect of aluminium on calcium homeostasis . . . . . . . . . . Aluminium induced apoptosis . . . . . . . . . . . . . . . . . . . . . . Aluminium induced inflammatory responses in the brain Aluminium induced neurofibrillary tangles (NFTs) . . . . . Other aluminium induced changes in the brain . . . . . . . . Animal models for aluminium toxicity . . . . . . . . . . . . . . . Caenorhabditis elegans model . . . . . . . . . . . . . . . . 12.1. Fruit fly (Drosophila melanogaster) . . . . . . . . . . . 12.2. Rats (Rattus norvigicus) . . . . . . . . . . . . . . . . . . . . . 12.3. Mouse (Mus musculus) . . . . . . . . . . . . . . . . . . . . . 12.4. Rabbits (Oryctolagus cuniculus) . . . . . . . . . . . . . . 12.5.

* Corresponding author. E-mail address: [email protected] (T. Prakash). http://dx.doi.org/10.1016/j.biopha.2016.07.035 0753-3322/ã 2016 Elsevier Masson SAS. All rights reserved.

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Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752

1. Introduction Al, the third most abundant element and the most common metal in the earth's crust and it is ubiquitous in the environment. Al toxicity only happens when exposure to an extremely high level of Al content and it is unavoidable. Al enters into the human body through drinking water, food, use of utensils, deodorants, and drugs [1]. It is estimated that the dietary intake of Al can be from 3 to 30 mg/day [2]. Most of the Al compounds are relatively insoluble at physiological pH, limiting absorption of Al through ingestion or inhalation (only 0.06% to 0.1% absorbed). Al toxicity results due to an exposure to large amounts of Al containing compounds or direct inoculation of Al via dialysates, parenteral nutrition, or implanted foreign materials, such as surgical cements. In the brain Al accumulates in the sensitive area such as hippocampus and frontal cortex and is considered as a contributing factor in the pathogenesis of neurodegenerative diseases [1]. Normally Al has no known physiological role. The toxic consequences of Al exposure are thought to be related to dysregulation of other essential metals or ions; deposition of insoluble Al precipitates in vulnerable tissues; or proteins, lipids, or nucleotic interactions resulting in conformational and structural alterations, aggregation, and functional alterations. Neurological consequences of toxic Al exposure include Encephalopathy, Seizures, Motor neuron degeneration, Parkinsonism and death. Al mediated neurodegeneration resulting in cognitive dysfunction has been associated with elevated amyloid precursor protein (APP) expression [3,4], amyloid b (Ab) deposition [5,6], impaired cholinergic projections and apoptotic neuronal death [7–9]. Al toxicity generally caused by the disruption of homeostasis of metals such as magnesium, calcium, and iron: in fact, Al mimics these metals in their biological functions and triggers many biochemical alterations [10]. Al exerts direct genotoxicity in primary human neuronal cells and induces neurodegeneration, through an increase in iron accumulation and oxygen reactive species (ROS) production [11]. Al induces neurotoxicity primarily by triggering oxidative stress that affects a large number of signaling cascades and ultimately causes cellular death. Al induced

oxidative damage to DNA has been previously associated with neurodegeneration in different regions of the rat brain [12]. Most of the studies suggests that the removal of toxic metal from human body can represent a useful tool to avoid the beginning or progression of many diseases related to metal intoxication [13]. 2. Aluminium-induced oxidative stress Al chloride accelerates iron mediated lipid peroxidation (LPO) and the results marked oxidative damage by increasing the redox active iron concentration in the brain. Increased Oxy-radicals and loss of cellular homeostasis cause oxidative stress that leads to neurotoxicity [14]. The oxidative products released in the neurons are malondialdehyde, carbonyls, peroxynitriles, nitrotyrosines, and enzymes like super oxide dismutase (SOD), haemoxygenase-I, etc. [15]. The imbalance in oxidative oxidant-antioxidant status mainly characterized by increased LPO and a decreased level of antioxidant enzymes. Al chloride can able to react with superoxide anions, which are more potent oxidants. Al levels and its relation to oxidative stress has been reported in glia, astrocytes and microglia [16]. Primarily under oxidative stress conditions, SOD act as a first line defense against superoxide as it converts the superoxide anion to hydrogen peroxide (H2O2) and oxygen (O2). It can also detoxify superoxide radical to H2O2, which is then converted to H2O by catalase (CAT) at the expenditure of reduces glutathione (GSH). Glutathione in its reduced form is the most abundant intracellular antioxidant and is involved in the direct scavenging of free radicals or serving as a substrate for the glutathione peroxidase enzyme that catalyzes the detoxification of H2O2 [17] . Glutathione-stransferase (GST) also helps in the detoxification of ROS by maintaining a metabolic intermediate such as GSH [14]. Al alters the cellular redox state by inhibiting the enzymes involved in antioxidant defense which functions as blockers of free radical processes. There will be a significant decreased in the activities of SOD in cerebrum, cerebral hemisphere and brain stem after Al exposure [18]. Al can bind to negatively charged brain phospholipids, which contain polyunsaturated fatty acids and are

Fig. 1. Diagrammatic representation of aluminium, ROS, anti-oxidative enzymes and lipid peroxidation. TBARS—Thiobarbituric acid reactive substances, SOD—Superoxide dismutase, GPx—Glutathione peroxidase, GSSG—Oxidized glutathione. Adapted from the research findings of Exley [20]; Halliwell and Gutteridge [23]).

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easily attacked by reactive oxygen species such as O2, H2O2, and OH [19]. Al stimulates iron-initiated lipid peroxidation in the Fenton reaction, which causes ROS production and Fe3+ formation. Superoxide is neutralized by Al3+ to form an Al-O2 complex, which increases the oxidative capacity of O2 [20]. ROS may also cause cellular damage, by oxidizing amino acid residues on proteins, forming protein carbonyls [21]. The relation between among the Al, ROS, anti-oxidative enzymes and lipid peroxidation were diagrammatically represented in Fig. 1 (Adapted from the research findings of Exley [20]; Halliwell and Gutteridge [23]). 3. Aluminium as a cholinotoxic agent Cholinergic functions of the central nervous system (CNS) mainly depend on the neurotransmitter acetylcholine (ACh). After release from presynaptic nerve terminals, ACh is rapidly removed from the synaptic cleft by Acetylcholine esterase (AChE), which belongs to the family of type B carboxyl esterases and cleaves ACh into inactive metabolites, choline and acetate [22]. As cholinotoxic, Al chloride produces functional change in the cholinergic and noradrenergic neurotransmission. AChE is responsible for the acetylcholine metabolism whose alterations caused neurobehavioral changes especially memory and cognitive function. AChE catalyzes the hydrolysis of acetylcholine into inactive metabolites, choline and acetate [14]. Due to the long time exposure to the Al there will be an increased amount of production of enzymes or stress by increasing the protein content, the later fall in tissue protein reflects the possible adverse impact during continued exposure [22]. Slow accumulation of Al in the brain and formation of Al complex with high affinity for the anionic site of enzyme increase the free radical production and promote oxidative stress [23]. Finally, free radical production accompanied by brain AChE activity shows the possible cholinergic dysfunction and indicating that the cholinotoxic potential of the Al as a consequence of oxidative stress. 4. Aluminium induced neurotoxicity Al is reported to influence a number of important reaction and it results various adverse effects on the mammalian Central nervous system (CNS). It includes important reactions for brain development such as the axonal transport, neurotransmitter synthesis, synaptic transmission phosphorylation or dephosphorylation of proteins, protein degradation, gene expression, and inflammatory responses. Al exhibits in only one oxidation, Al3+. It has a greater affinity towards negatively charged, oxygen-donor ligands. Other groups like inorganic and organic phosphates, carboxylate, and deprotonated hydroxyl groups form a strong bond with Al3+. These possible characteristics of Al3+ makes a strong bonding with phosphate

Reactive oxygen species and reactive nitrogen species/lipd peroxidation products (4-HNE)

5. Aluminium on gene expression Al affect gene expression by altering the expression of cerebral proteases and by activating monoamine oxidase isotypes in brain [24]. Al binds to the histone-DNA complex and induces conformational changes and also induces topological changes of DNA [25– 27]. The studies show that there is an elevated level of glial cell marker TNF-a and glial fibrillary acidic protein (GFAP) [28]. Also Al induces the expression of NF-kB subunits, interleukin-1b precursor, phospholipase A2 and DAXX that involved in the proinflammatory and pro-apoptotic signaling mechanisms [29]. The altered gene expression induces the decreased expression of neurofilament, tubulin, AbPP (Amyloid b protein precursor) and neuron specific enolase [30,31]. Studies also shows that the Al induces the lowering number of mitochondrial cytochrome c oxidase receptors and decreases the expression of neuron growth factor (NGF) and brain derived neurotrophic factor (BDNF) [32]. The probable mechanism of altering the gene expression is by binding to proteins involved in the gene expression. Al binds to the transcription factor IIIA in the zinc finger domain and inhibits its promoter binding [33]. Also, the studies show that Al at low concentration unwinds the supercoiled DNA irreversibly and at high concentration decreases the rate of replication [34,35]. Al binds to the phosphate group of the DNA backbone and at the N-7 position of guanine in GC rich base pairs [36]. Al enhances Tm of oligonucleotides d (GCCCATGGGC) and d(CCGGGCCCGG) in low concentrations. It

Microglial activation

Aluminium

Reduced SOD, Catalase, GSHPX, GSH and glutamate

groups of DNA and RNA, affecting DNA topology and influencing the expression of various gene essential for brain functions. Al3+ also binds with phosphate groups of nucleoside di- and triphosphates, such as ATP and can thus influence energy metabolism. Furthermore, as the Al3+ has strong positive charge and small ionic radius in comparison to Ca2+, Zn2+, and Na+. Hence, Al3+ strongly binds to metal-binding amino acids (histidine, tyrosine, arginine, etc.) or phosphorylated amino acids and acts as a cross-linker. Finally, it results oligomerization of proteins, inducing conformational changes that can inhibit their degradation by proteases [10]. Strong binding of Al3+ to phosphorylated amino acids promotes the self-aggregation and accumulation of highly phosphorylated cytoskeleton proteins, including neurofilament and microtubule-associated proteins (MAPs). Finally, Al results apoptotic death of neurons and glial cells. It also impairs enzymes that involved in the neurotransmitter synthesis and thus affects the neurotransmitter content. Al3+ also inhibits voltage gated Ca2+ channels and neurotransmitter receptors, and impairs synaptic transmission. All of these Al3+ characteristics finally results in to neurotoxicity, neurodegeneration and impairs various brain functions related to learning and memory [10].

Mitochondrial dysfunction

Excitotoxicity

Impaired glutamate transporters

Fig. 2. Diagrammatic representation of possible mechanisms of aluminium on neuroexictotoxicity.

S. Maya et al. / Biomedicine & Pharmacotherapy 83 (2016) 746–754

also induces conformation (which is a rare phenomenon) in these oligonucleotides [37]. The conformational changes induced by the Al enhance susceptibility to DNA damage and gene expression changes that might lead to neuronal cell death in neurodegeneration. 6. Effect of aluminium on cell mediated excitotoxicity Al causes the mitochondrial damage leading to the generation of highly reactive oxy and hydroxyl free radicals and cause accumulation of hydrogen peroxide. The increased hydrogen peroxide pool enhances the presence of redox active iron either from loosely bound iron or by modulating the electron transport chain [38]. Also Al enhances oxidative stress through enhanced iron-mediated Fenton reactions by increasing the redox active iron concentrations. Studies shows that Al activates superoxide dismutase, while it inhibits catalase [38,39]. Finally, this will result the enhancement of iron mediated oxidative stress. Furthermore, Al may potentiate the increase in glutamate induced excitotoxicity and it has been postulated that the neurotoxic effects of Al could be mediated through glutamate, an excitatory amino acid [40]. Al has been shown to interfere with the action of membrane receptors (i.e., G-protein coupled receptors (GPCR)), cell signaling pathways, alter DNA integrity and impair mitochondrial function, all of which will have an enhancing effect on excitotoxicity [41]. The possible mechanisms for neurodegenerative effects of Al as related to excitotoxicity is depicted in Fig. 2. 7. Effect of aluminium on calcium homeostasis Al also induce neuronal injury by interfering calcium homeostasis. Al delay the closure of voltage-dependent calcium channels and block calmodulin (CaM)-dependent Ca2+/Mg2+-ATPase, which is responsible for the protective mechanism against excitotoxicity [42]. The studies also show that, there is an increase in glutamate levels while their g-aminobutyric acid (GABA) brain levels were decreased, a condition that maximizes excitotoxic damage in rats [43]. Al rise to metabolic changes likewise, elevation of the resting Ca2+ and peak Ca2+ levels in neuronal cytoplasm, less Ca2+ influx, a modest inhibition of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phosphatidylinositol-specific phospholipase C (PIPLC) in phosphoinositide signaling pathways, resulting in less

Aluminium

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Inositol trisphosphate (IP3) formation, less Protein Kinase C (PKC) activation, and a slower rate of Ca2+ removal from the cytoplasm. Critical changes in the Ca2+ homeostasis and Ca2+ signaling could occur from the continued accumulation of Al in neurons and leading to the more extensive and disabling disruptions that affect Ca2+ metabolism in neurodegenerative diseases [44]. The possible pathways that the Al intervene in the process of neurodegenerative disease by altering Ca2+ homeostasis is depicted in Fig. 3. 8. Aluminium induced apoptosis Al induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation [8]. The released cytochrome c from mitochondria binds to Apaf-1 and initiates Al induced apoptosis cascade [45]. The formed complex activates caspase-9, that in turn activates the effector caspase that is caspase-3. The released cytochrome c involved in three distinct pathways like, opening of the mitochondrial transition pore (MTP), translocation of mitochondria of the pro-apoptogenic Bax which can form the channel by itself, and interaction of Bax with the voltage dependent anion channel (VDAC) to form a larger channel which is permeable to cytochrome c. The primary event in the apoptosis is considered as the mitochondrial changes following cytotoxic stimuli [2]. Furthermore, the studies show that the activation of SAPK/JNK (stress-activated protein kinase or c-jun N-terminal kinase) signal transduction pathway also caused by the induction of Al and results in apoptosis [46]. Apoptosis is believed to be the general mechanism of Al toxicity to the cells. Treatment with Al shows some characteristic features of apoptosis like shrinkage of cell bodies, hypercondensed and irregularly shaped chromatin and extensive fragmentation of chromatin and DNA [8,47]. Al induces apoptosis in the astrocytes further leading to the neuronal death by loss of the neurotrophic support [48]. 9. Aluminium induced inflammatory responses in the brain Most of the observations from the studies demonstrate aluminium induced inflammatory responses. Involvement of lipoxygenase and cyclooxygenase-mediated arachidonic acid turnover has been suggested in the Al-induced platelet activation [49]. Al was found to elevate the proinflammatory cytokines, TNFa, and IL-1a. When the brain cells getting injured, the intracellular

Hexokinase

ATP/ADP ratio

Na+-K+-ATPase

Loss of ionic homeostasis

Release of intracellular Ca2+

(Ca2+)ICF

Mitochondrial perturbation Oxidative stress

Failure of ATP- reliant ion transport pumps Depolarization

Release of glutamate

Excitotoxicity

Cell death

Membrane damage

Activation of phospholipase Aluminium

Fig. 3. Diagrammatic representation of possible pathways that the aluminium intervene in the process of neurodegenerative disease by altering Ca2+ homeostasis.

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Ca2+ rises and also produce reactive oxygen species. While potentially damaging via their direct actions, Ca2+ and free radicals can also activate neuroprotective transcription factors, including nuclear factor-kB (NF-kB), hypoxia-inducible factor 1(HIF1) and interferon regulatory factor-1 [50]. Al also reported to be responsible factor for the induction of HIF1 and NF-kB, via the same pathway, which in turn, may augment specific neuroinflammatory and pro-apoptotic signaling cascade. Through the activation of NF-kB, Al possibly brings out these changes in proinflammatory cytokines [50]. Several studies show that seven genes are significantly up-regulated by Al, which encode proinflammatory or pro-apoptotic signaling elements, including NFkB subunits, IL-1b precursor, cytosolic phospholipase A2, cyclooxygenase-2, beta-amyloid precursor protein and DAXX, a regulatory protein known to induce apoptosis and repress transcription [51]. 10. Aluminium induced neurofibrillary tangles (NFTs) NFTs are the aggregates of phosphorylated tau protein and found as a marker for neurodegenerative diseases, namely Alzheimer’s disease (AD) and ALS. The studies show that Aluminium can induce abnormality in cytoskeletal protein such as neurofilaments and/or tau, and causes the formation of NFT and neurodegeneration of motor neurons in ALS [52]. Tau is bound by microtubules in healthy neurons, and is essential to form and function of the neuronal cytoskeleton. Al-ATP, like glutamate, stimulates glutamate receptor activity and leads to an increased level of neuronal tau [53]. The important properties of the tau protein are its ability to self-assemble into filamentous structures that are the pathological hallmark of taupathies. Still the exact mechanism behind the abnormal accumulation of tau filaments are unclear, hence understanding the mechanism is crucial for potential therapeutic strategies [54]. The studies show that the Al induced tau aggregates are not in fibrillary form but appeared as amorphous form. Al can produce toxicity to the fibroblasts that expressed tau. However, tau did not aggregate in these cells, but neurofilaments do aggregate in aluminium-treated cells [55]. Also

the Al-induced increased in tau immunoreactivity was observed in human neuroblastoma cells, without an effect on cell viability [56]. Al causes the tau and neurofilament monomers in soluble form and which results the formation of aggregates in to non-fibrillar material. Al also induce to form fibrillary bundles of neurofilaments and to form NFTs [55,57]. Al induces hyperphosphorylation of tau by inhibiting Protein Phosphatase-2A (PP2A) activity in pyramidal cells. Al activates caspase which truncates hyperphosphorylated tau. Al then binds to the truncated hyperphosphorylated tau, and aggregates it into granules. When confluent, the aggregates appear as cytoplasmic pools. High local concentrations of Al/truncated hyperphosphorylated tau, may trigger polymerization. NFT filaments polymerize within the Al/ truncated hyperphosphorylated tau complex of the cytoplasmic pools. Some of the NFTs are get larger enough to enucleate and kill the neuron cells [58]. The evidence shows that in early stages of ALS, clusters of morphologically normal NF accumulate in the neuronal cell body and intraparenchymal axons of motor neurons [59,60]. The effect of aluminium in the formation of NFT is depicted in Fig. 4 (Adapted from the findings of Yokel [61]). 11. Other aluminium induced changes in the brain Some studies show that there is an increase in prostaglandin E2 (PGE2), prostaglandin A1 (PGA1), and thromboxane A2 (TXA2) in rat hippocampus [62]. The exact mechanism behind the prostaglandin induced neurodegeneration is still unknown. But the studies show that apart from prostaglandin, thromboxane, and cytokine receptors, toll-like receptors (TLRs), on both glia and neurons that likely mediate the neuroinflammatory responses. PGE2, one of the product of inflammatory reactions, and PGA1, which is formed during PGE2 extraction, induce degeneration in adenosine 30 ,50 -cyclic monophosphate (cAMP)-induced differentiated neuroblastoma cells in culture. The mechanism behind the neurodegeneration may be the increase in oxidative stress. PGE2/ PGA1 increases the expression of CAT and decrease the expression of glutathione peroxidase (GPx1), mitochondrial superoxide

Tau Protein (τ, 52-68 kD MAP)

Phosphorylation Al

Hyperphosphorylated tau

P

P

P

P Al

Aggregation of insoluble form

Intra neuronal paired helical Filament tau (PHFτ) Al binds/stabilizes, Neurofibrillary Tangles (NFTs) Fig. 4. Aluminium induced NFT formation. By phosphorylation tau protein turns to hyperphosphorylated and aggregated to form neurofibrillary tangles in neurodegenerative diseases. Increased Al enhances the formation of NFTs.

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dismutase (Mn-SOD2). These will change in levels of CAT, GPx1, and Mn-SOD1 may make the cells more sensitive to oxidative damage [63]. Also studies show an elevated serum and CSF PGE2 concentration in ALS patients, and suggests that the neurodegeneration is mainly through the oxidative damage of neurons and glutamate mediated-excitotoxicity [64]. Furthermore, Prostaglandin E2 receptor 1 (EP1) activation shown to mediate Ca2+ dependent neurotoxicity in ischemic injury [65]. Prostaglandin E2 receptor 2 (EP2) activation also shown to mediate microglialinduced paracrine neurotoxicity as well as suppress microglia internalization of aggregated neurotoxic peptides [65]. Also, microglial EP2 contributed to a-synuclein aggregation and associated neurotoxicity as well as microglial activation [66]. The thromboxane receptor (TP) activation increases the b-amyloid peptides and secreted amyloid precursor protein (APP) ectodomains. This increase was a result of increased APP mRNA stability leads to the elevation of APP mRNA and protein levels. This increase in APP provide more substrate for a- and bsecretase proteolytic cleavages, thereby increase the b-amyloid generation and amyloid plaque deposition [67]. This mechanism also considered as one of the etiopathology for neurodegenerative diseases. 12. Animal models for aluminium toxicity Although Al3+ exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanisms behind the Al3+ transport in neurons and subsequent neuron damage has remained elusive [68]. This review describes some animal models for Al induced neurotoxicity or neurodegeneration 12.1. Caenorhabditis elegans model C. elegans, has been used as a tool to probe for mechanisms underlying numerous neurodegenerative diseases. C. elegans have approximately 60–80% of human genes and contain genes involved in metal homeostasis and transport, allowing for the study of metal-induced degeneration in the nematode. The small size, low culture cost and fast life-cycle of the worm is an advantage for the studies, as it allows for easy maintenance. Also, the C. elegans are transparent in nature, which helps in vivo study with fluorescent reporters, such as green and red fluorescent proteins. Apart from these, the simple, but complete nervous system with four functional categories of neurons based on their circuity: motor neurons, sensory neurons, inter neurons, and polymodal neurons, which makes easy to investigate neurological function in C. elegans. The worm has 302 neurons and about 5000 synapses [69], it shares similar neurotransmitters with humans, including dopamine (DA), acetylcholine (ACh), serotonin (5-HT), g-aminobutyric acid (GABA), glutamate, and others. The biosynthesis and transport of neurotransmitters are conserved in the nematode and human nervous system [70]. C. elegans have eight DAergic neurons; two pairs of cephalic (CEP) neurons, a pair of anterior deirid (ADE), and a pair of postdeirid (PDE) neurons [71–73]. GABAergic neurons in C. elegans consists of 26 neurons and categorized under six types, DD, VD, RME, RIS, AVL, and DVB, based on their synaptic output. DD and VD innervate the dorsal and ventral body muscles, RME innervate the head and AVL and DVB innervate the enteric muscles and RIS are interneurons [69]. The locomotor behaviors are the most commonly used analysis for neurodegeneration and application of exogenous 5-HT inhibits locomotion, but stimulates egg-laying and pharyngeal pumping [74–78]. C. elegans are expressed with excitatory and inhibitory ionotropic glutamate receptors (iGluRs) and mediate 10 putative iGluR subunits, namely glr 1–8 and nmr 1–2. Also, six of the

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subunits, including glr-1, glr-2, glr-4, glr-5, nmr-1, and nmr-2, are expressed in C. elegans interneurons [79,80]. Al exposure decreases mitochondrial membrane potential and cellular ATP levels, and confers DA neuron degeneration in the genetically tractable C. elegans. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. The cell death in the nematode is due to a reduction in the gene expression of the vertebrate apoptotic caspase homologue Apaf1 and ced-4 [62]. 12.2. Fruit fly (Drosophila melanogaster) Drosophila is one of the most well understood of all the model organisms having a life span about 40–50 days in optimal temperature. Depending on diet and stress the life span ranges up to an average of 120 days [81]. The Drosophila genes are so close to human genes, including disease genes and can be matched with equivalent genes in the fly [82]. The laboratory maintenance of Drosophila is inexpensive and its short life span makes an advantage in biomedical research, especially in the field of neurodegenerative diseases. The fly’s behavior ranges from simple avoidance to learning and memory [83]. Typical neurodegenerative phenotypes like reduced life span, locomotor deficits, olfactory learning abnormalities and vacuolization of the brain were observed after feeding Drosophila with excess amount of Al [84]. On the exposure to Al, general neurodegeneration and several behavioral changes were observed in Drosophila and the flies accumulated with large amount of iron, ROS, and exhibited elevated SOD2 activity. The further observations indicate that the Al-neurodegeneration is independent of b-amyloid and tauassociated toxicity [84]. Further studies show that the excess concentration of Al in Drosophila significantly decreases the life span of Drosophila due to significant reduction in the Na content of the flies due to Na efflux, also it increases rigidity of the cell membrane and alters the locomotor activity depending up on the age of Drosophila [85,86]. Al also decreases the activity of ATPase and it binds to the calmodulin, changes in the protein conformation and loss of the a-helix structure results [87]. Thus the in vivo studies by using Drosophila might help in drug development in neurodegenerative diseases [88]. 12.3. Rats (Rattus norvigicus) Rats were the one of the most widely used organism in medical research. In studies of cognition and memory, the rats are the best model when comparing in to other models, because the physiological systems involved in learning and memory have been so extensively studied in this animal. The rat is more intelligent than the mouse and is capable of learning a wide variety of tasks that are necessary for a cognitive research [89]. Thus the rats have been used as an animal model for physiology, pharmacology, toxicology, nutrition, behavior, immunology, and neoplasia [90]. Over 500 inbred rat strains have been developed for a wide range of biochemical and physiological phenotypes and different disease models [91]. Studies shows that exposure to Al, changes in the level of 5-hydroxytrytamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) levels in the rat’s olfactory lobe (OLB), cerebellum (CBL), pons (PON), medulla oblongata (MOB), spinal cord (SPI), hypothalamus (HYP), hippocampus (HIP), striatum (STR), midbrain (MBR) and cortex (COR) brain regions. The toxicity is depending up on the duration of exposure and the brain-region specific [92]. Al exposure also promotes the oxidative stress in the striatum and it at as a prooxidant in rat brain by inhibiting the enzymes SOD and CAT [93,94]. Al further decreases the level of reduced glutathione,

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glutathione peroxidase, glutathione reductase, Na(+)K(+)ATPase and Mg2+ATPase and increases the level of lipid peroxidation and the activities of alkaline phosphatase, acid phosphatase, alanine transaminase and aspartate transaminase in all brain regions of rat brain [95]. In aged rats, Al administration will alter the levels of copper, zinc, and manganese in certain brain regions and resulted in an enlargement of hippocampal mossy fibers [96]. Furthermore, Al induces neuronal apoptosis and cognitive dysfunction of hippocampus and cortex in rats. Al alter the Bcl-xl, bcl-2 and Caspase-3 protein and mRNA expressions of hippocampus and cerebral cortex of rats [97]. Excess Al in the brain will change in behavior, long term memory and intellectual in animals due to endorsed aggregation of b-amyloid protein and acetylcholinesterase activity. These mechanisms finally lead to neurotoxicity and cerebral damage in rat brain [98,99]. Al administration decreases the Ca2+ ATPase activity whereas increases the levels of 30 , 50 -cyclic adenosine monophosphate, intracellular calcium and total calcium content in both the cerebrum and cerebellum of rats. Also, Al exposure significantly elevates the protein expressions of phospholipase C, inositol triphosphate and protein kinase A but decline the expressions of protein kinase C [100]. Apart from these Al treated rat shows an increase in prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), thromboxane A2 (TXA2), prostacyclin (PGI2) and prostaglandin F2a (PGF2a) in rat hippocampus. The prostaglandin D2 receptor 1 (DP1), prostaglandin E2 receptor 2 (EP2), prostacyclin receptor (IP), microsomal prostaglandin E2 synthase-1 (mPGES-1), Prostaglandin E2 receptor 4 (EP4), prostacyclin synthase (PGIS) and thromboxane A synthase (TXAS) mRNA expressions were also increased in Al treated rats, while the prostaglandin E2 receptor 3 (EP3) and FP mRNA and protein expressions and thymidine phosphorylase mRNA (TP mRNA) expressions were decreased in the hippocampus of rat [62]. So, the long term Al exposure may lead to electrophysiological, cognitive and biological modifications in the whole brain of rats [101]. 12.4. Mouse (Mus musculus) These are the one of the most commonly used mammalian research model and used for research in neurodegenerative disease. Studies shows that mouse zona compacta neurons exhibit the same electrophysiological and pharmacological properties as rat dopamine-containing neurons [102]. Al exposure alters the major chemical constituents, such as lipids, proteins and nucleic acids of the brain of mice [103]. Chronic Al administration results in significant motor incoordination and memory deficits, which were also endorsed biochemically as there was increased oxidative stress as well as elevated acetylcholinesterase (AChE) and Al level in the brain. Al also causes decreased vacuolated cytoplasm as well as decreased pyramidal cells in the hippocampal area of mice brain [104]. The further studies shows that Al exposure shows a decrease in the activity of the antioxidant enzymes such as SOD, CAT, GSHPx in the Al treated Balb/c and C57BL/6 mice. Also, there is an increase in lipid peroxidation was reported in the mice [105]. Al administration results a deposition of Ab which were largely confined to vascular area and at the bifurcations of the vessels [106]. 12.5. Rabbits (Oryctolagus cuniculus) Rabbits have proven to be especially sensitive to Al exposure, with intracerebral and intravenous infusions reproducing some of the pathological features consistent with AD [107]. Studies shows that aluminium exposure induced neurocytoskeletal changes in fetal rabbit midbrain in matrix culture and reported the Al-induced neurofibrillary tangle formation in rabbit

midbrain [108]. Furthermore, the studies show that Al induces mitochondrial and endoplasmic reticulum stress in rabbit brain [45]. These evidence suggesting that Al induced mitochondrial and endoplasmic reticulum mediated apoptosis cascade is the one of the major pathway in the neurodegenerative diseases. The rabbit studies also show a changes in hemato-biochemical parameters, lipid peroxidation and enzyme activities due to Al administration. Al induces free radicals and decreases the activity of GST and the levels of sulfhydryl groups (SH) in rabbit plasma, liver, brain, testes and kidney. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), acid phosphatase (AcP), and phosphorylase activities were significantly decreased in liver and testes. While brain lactate dehydrogenase (LDH) activities were significantly increased. Also, the activity of AChE in brain and plasma were decreased in rabbits due to Al exposure [39]. 13. Summary Although there is lots of evidence that implicates Al in the progression of events that leads to neurodegenerative diseases, some of the evidence remains controversial. However, it is widely accepted that Al is a recognized neurotoxin and that could cause neurodegeneration. Al is a highly abundant and ubiquitously distributed as environmental and industrial toxicant and is also contained in many food products, being involved in skeletal, hematological, and neurological diseases. Once Al reached inside the human body in large amount it can potentiate the formation of ROS, and activate glial cells. Further the ROS generated and inflammatory events initiated and finally leads to cell death. Al toxicity also caused by the disruption of homeostasis of calcium and other metals such as iron and magnesium. We have summarized various hypothesis that link between Al and neurodegeneration. The summarizes that Al causes neurotoxicity in multifaceted way by modulating DNA repair enzyme inhibition, enhancement of ROS production, reduction of antioxidant enzymes and its actions, and alterations of pathways like NF-kB, JNK, DNA binding etc. Furthermore, the Al can produce cross-linking of DNA strands We thank Premanath Reddy, Chairman, and Shalini Reddy, Secretary, Acharya Institute, Bangalore for providing the facilities and support to carry out the study on neurodegenerative disease[109], affect the activity of a number of enzyme systems [110] including enzymes involved in the neurotransmitter function [111–114], and can bind competitively with calmodulin and affect its structural configuration [115,116]. All these events finally lead to genomic instability, cell death and neurodegeneration. So, it is clear that further scientific studies are essential against this problem to discover better ways to detect, treat, and prevent the progression of Al induced neurodegenerative disease like ALS. References [1] M. Nampoothiri, J. John, N. Kumar, J. Mudgal, G.K. Nampurath, M.R. Chamallamudi, Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats, Behav. Neurol. 2015 (2015) 1–9. [2] Bharathi, P. Vasudevaraju, M. Govindaraju, A.P. Palaniswamy, K. Sambamurti, K.S.J. Rao, Molecular toxicity of aluminium in relation to neurodegeneration, Ind. J. Med. Res. 128 (2008) 545–556. [3] R. Lin, X. Chen, W. Li, Y. Han, P. Liu, R. Pi, Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by curcumin, Neurosci. Lett. 440 (2008) 344–347. [4] J.R. Walton, M.X. Wang, APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease, J. Inorg. Biochem. 103 (2009) 1548–1554. [5] A. Campbell, A. Kumar, F.G. La Rosa, K.N. Prasad, S.C. Bondy, Aluminum increases levels of beta-amyloid and ubiquitin in neuroblastoma but not in glioma cells, Proc. Soc. Exp. Biol. Med. 223 (2000) 397–402.

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