References (1) Nucleus and gene expression.   Binding to DNA   Binds to histone-DNA complex and induces conformational changes of chromatin. [20] Induces topological changes of DNA. [21,22]   Altered gene expression.   Induces decreased expression of neurofilament and tubulin. [23] Induces altered expression of genes of neurofilament, APP, and neuron specific enolase. [24] Induces decreased expression of transferrin receptor. [25] Induces altered expression of RNA polymerase I. [26] Induces downregulation of mitochondrial cytochrome c oxidase. [27] Induces altered expression of calbindin-D28k. [28] Induces decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). [29] Induces expression of pro-inflammatory genes and pro-apoptotic genes. [30] Induces elevated expression of APP. [31,32] Induces altered expression of oxidative stress marker genes (SOD1, glutathione reductase, etc.). [33] Induces decreased expression of neprilysin. [34] Induces altered expression of β-APP secretase (BACE1 and BACE2). [35]   (2) Cellular functions   Energy metabolismo   Inhibits the activity of hexokinase [36] Inhibits the activity of phosphofructokinase [37] Inhibits the activity of glucose-6-phosphate dehydrogenase [38] Causes mitochondrial dysfunction and depletion of ATP [39,40] Decreases in activity and expression of TCA-cycle related enzymes (succinate dehydrogenase (SDH), alpha-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase-NAD+ IDH), fumarase (FUM), aconitase (ACN), and cytochrome c oxidase (Cyt C Ox)). [41]   Phosphorylation and dephosphorylation   Inhibits the activity of protein phosphatase. [42] Increases the activity of protein kinase C and cytoskeleton proteins. [43] Accelerates phosphorylation and accumulation of neurofilament. [44] Enhances Ca2+/Calmodulin dependent protein kinase activity. [45] Accelerates phosphorylation of MAP 2 and neurofilament. [46] Inhibits dephosphorylation of tau. [47] Induces nonenzymatic phosphorylation of tau. [48]   Abnormal accumulation of proteins   Causes the conformational change and the accumulation of neurofilament and MAP1A, MAP1B. [49] Accelerates the phosphorylation of tau and its accumulation. [50] Causes the accumulation of tau protein in neuroblastoma cells or in primary cultured neurons. [51,52] Causes the accumulation of tau protein in experimental animals. [53,54] Causes neurofibrillary degeneration in vivo. [55] Causes the accumulation of AβP in cultured neurons or in neuroblastoma cells. [56,57] Causes the accumulation of AβP in vivo. [58,59]   Neurotransmitter release   Inhibits glutamate release. [60] Impairs synaptic transmission. [61,62] Inactivates glutamate dehydrogenase. [63] Inhibits NMDA-type glutamate receptor. [64] Inhibits choline acetyl transferase and tyrosine hydroxylase, glutamate decarboxylase. [65,66] Influences acetyl-CoA and inhibits acetylcholine release. [67] Activates monoamine oxidase. [68,69] Inhibits dopamine beta-hydroxylase. [70] Inhibits uptake of serotonin and noradrenalin in synaptosomes. [71]   Channel inhibition   Influences the activities of Na+ channels and K+ channels. [72] Enhances the voltage-activated Na+ channels. [73] Inhibits the voltage-gated calcium channel. [62,74] Inhibits the IP3-mediated Ca2+ release. [75]   Others   Influences GTP binding proteins as aluminum fluoride. [76] Inhibits GAP junction. [77] Inhibits axonal transports. [78] Binds to calmodulin and inhibition of calmodulin-binding enzymes. [79] Induces inflammatory responses. [80]   (3) Membrane lipids     Peroxidation   Accelerates iron-induced membrane lipid peroxidation. [81] Enhances lipid peroxidation in liposomes. [82] Induces peroxidation of myelin lipids in vivo. [83] Increases peroxidation products (malondialdehyde). [50]   Membrane properties   Causes the change the lipid/phospholipids profiles of myelinin vivo. [84] Induces the change in membrane physical properties (surface potential, lipid fluidity, and lipid arrangement). [83] Induces the change of membrane fluidity. [85]   (4) Higher functions     Cell death   Causes the apoptotic neuronal death. [86,87] Causes the apoptosis of astrocytes. [88] Causes the death of motor neuron. [89,90]   Behavior, learning, and memory, others   Inhibits long term potentiation (LTP). [91,92] Causes learning disorder or memory deficit in experimental animals. [93–95] Influences electrical activity in hippocampus and inhibits spatial learning memory deficit in aging rats. [96] Causes memory deficit in AD model mice. [97,98] Causes encephalopathy in dialysis patients. [99] Causes encephalopathy in patients with renal failure. [100]

Table 1: Effects of aluminum on the development of the central nervous system.

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