Fig. 1

Potential role of excess zinc in Alzheimer’s disease pathology. Zinc is released from synaptic vesicles in response to neuronal activity. Three main mechanisms have been proposed for how excess zinc can contribute to AD. (1) Zinc can accumulate bound to Aβ at zinc-secreting synapses promoting the formation of protease resistant oligomers and fibrils forming senile plaques. Aβ oligomers stimulate NMDAR-dependent increase in cellular calcium, leading to activation of NADPH oxidase (NOX) and nitric oxide synthase (NOS) generating oxidant species (superoxide anion and nitric oxide). (2) Zinc can inhibit the iron export ferroxidase activity of APP, leading to the accumulation of ferrous iron in neurons and potentially to oxidative stress. (3) Zinc stimulates kinases and inhibits protein phosphatases leading to phosphorylation of Tau which promotes the aggregation of Tau in neurofibrillary tangles (NFT) and contributes to a positive feedback loop that further increases postsynaptic calcium influx through NMDARs resulting in neuronal cell death