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
-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 A
P in cultured neurons or in neuroblastoma cells. [64 , 65 ] Causes the accumulation of A
P 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 ]
