Table 1.

Effects of aluminum on the central nervous system.

	References
(1) Nucleus and gene expression
Binding to DNA
Binds to histone-DNA complex and induces conformational changes of chromatin.	[29]
Induces topological changes of DNA.	[30, 31]
Altered gene expression
Induces decreased expression of neurofilament and tubulin.	[32]
Induces altered expression of genes of neurofilament, APP, and neuron specific enolase.	[33]
Induces decreased expression of transferrin receptor.	[34]
Induces altered expression of RNA polymerase I.	[35]
Induces downregulation of mitochondrial cytochrome c oxidase.	[36]
Induces altered expression of calbindin-D28k.	[37]
Induces decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF).	[38]
Induces expression of pro-inflammatory genes and pro-apoptotic genes.	[39]
Induces elevated expression of APP.	[40, 41]
Induces altered expression of oxidative stress marker genes (SOD1, glutathione reductase, etc.).	[42]
Induces decreased expression of neprilysin.	[43]
Induces altered expression of β-APP secretase (BACE1 and BACE2).	[40, 44]
(2) Cellular functions
Energy metabolism
Inhibits the activity of hexokinase	[45]
Inhibits the activity of phosphofructokinase	[46]
Inhibits the activity of glucose-6-phosphate dehydrogenase	[47]
Causes mitochondrial dysfunction and depletion of ATP	[48, 49]
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)).	[50]
Phosphorylation and dephosphorylation
Inhibits the activity of protein phosphatase.	[51]
Increases the activity of protein kinase C and cytoskeleton proteins.	[52]
Accelerates phosphorylation and accumulation of neurofilament.	[53]
Enhances Ca2+/Calmodulin dependent protein kinase activity.	[54]
Accelerates phosphorylation of MAP 2 and neurofilament.	[55]
Inhibits dephosphorylation of tau.	[56]
Induces nonenzymatic phosphorylation of tau.	[57]
Abnormal accumulation of proteins
Causes the conformational change and the accumulation of neurofilament and MAP1A, MAP1B.	[58]
Accelerates the phosphorylation of tau and its accumulation.	[59]
Causes the accumulation of tau protein in neuroblastoma cells or in primary cultured neurons.	[60, 61]
Causes the accumulation of tau protein in experimental animals.	[33, 62, 63]
Causes neurofibrillary degeneration in vivo.	[9]
Causes the accumulation of AβP in cultured neurons or in neuroblastoma cells.	[64, 65]
Causes the accumulation of AβP in vivo.	[44, 66, 67]
Neurotransmitter release
Inhibits glutamate release.	[68]
Impairs synaptic transmission.	[69, 70]
Inactivates glutamate dehydrogenase.	[71]
Inhibits NMDA-type glutamate receptor.	[72]
Inhibits choline acetyl transferase and tyrosine hydroxylase, glutamate decarboxylase.	[73, 74]
Influences acetyl-CoA and inhibits acetylcholine release.	[75]
Activates monoamine oxidase.	[76, 77]
Inhibits dopamine beta-hydroxylase.	[78]
Inhibits uptake of serotonin and noradrenalin in synaptosomes.	[79]
Channel inhibition
Influences the activities of Na+ channels and K+ channels.	[80]
Enhances the voltage-activated Na+ channels.	[81]
Inhibits the voltage-gated calcium channel.	[70, 82]
Inhibits the IP3-mediated Ca2+ release.	[83]
Others
Influences GTP binding proteins as aluminum fluoride.	[84]
Inhibits GAP junction.	[85]
Inhibits axonal transports.	[86]
Binds to calmodulin and inhibition of calmodulin-binding enzymes.	[87]
Induces inflammatory responses.	[88]
(3) Membrane lipids
Peroxidation
Accelerates iron-induced membrane lipid peroxidation.	[89]
Enhances lipid peroxidation in liposomes.	[90]
Induces peroxidation of myelin lipids in vivo.	[91]
Increases peroxidation products (malondialdehyde).	[59]
Membrane properties
Causes the change the lipid/phospholipids profiles of myelin in vivo.	[92]
Induces the change in membrane physical properties (surface potential, lipid fluidity, and lipid arrangement).	[91]
Induces the change of membrane fluidity.	[93]
(4) Higher functions
Cell death
Causes the apoptotic neuronal death.	[94, 95]
Causes the apoptosis of astrocytes.	[96]
Causes the death of motor neuron.	[97, 98]
Behavior, learning, and memory, others
Inhibits long term potentiation (LTP).	[99, 100]
Causes learning disorder or memory deficit in experimental animals.	[101–103]
Influences electrical activity in hippocampus and inhibits spatial learning memory deficit in aging rats.	[104]
Causes memory deficit in AD model mice.	[105, 106]
Causes encephalopathy in dialysis patients.	[20]
Causes encephalopathy in patients with renal failure.	[107]