Extracellular Zn2+-Dependent Amyloid-β1-42 Neurotoxicity in Alzheimer's Disease Pathogenesis

The basal level of extracellular Zn2+ is in the range of low nanomolar ( 10 nM) in the hippocampus. However, extracellular Zn2+ dynamics plays a key role for not only cognitive activity but also cognitive decline. Extracellular Zn2+ dynamics is modified by glutamatergic synapse excitation and the presence of amyloid-beta(1-42) (A beta(1-42)), a causative peptide in Alzheimer's disease (AD). When human A beta(1-42) reaches high picomolar (> 100 pM) in the extracellular compartment of the rat dentate gyrus, Zn-A beta(1-42) complexes are readily formed and taken up into dentate granule cells, followed by A beta(1-42)-induced cognitive decline that is linked with Zn2+ released from intracellular Zn-A beta(1-42) complexes. A beta(1-42)-induced intracellular Zn2+ toxicity is accelerated with aging because of age-related increase in extracellular Zn2+. The recent findings suggest that A beta(1-42) secreted continuously from neuron terminals causes age-related cognitive decline and neurodegeneration via intracellular Zn2+ dysregulation. On the other hand, metallothioneins (MTs), zinc-binding proteins, quickly serve for intracellular Zn2+-buffering under acute intracellular Zn2+ dysregulation. On the basis of the idea that the defense strategy against A beta(1-42)-induced pathogenesis leads to preventing the AD development, this review deals with extracellular Zn2+-dependent A beta(1-42) neurotoxicity, which is accelerated with aging.

Automated summary

The extracellular dynamics of Zn2+ in the hippocampus is influenced by glutamatergic synapse excitation and the presence of the Alzheimer's disease causative peptide Aβ(1-42), leading to cognitive decline. Aging accelerates Aβ(1-42)-induced intracellular Zn2+ toxicity due to an increase in extracellular Zn2+. Metallothioneins can serve as buffers for intracellular Zn2+ dysregulation caused by Aβ(1-42).