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-β1-42 (Aβ1-42), a causative peptide in Alzheimer's disease (AD). When human Aβ1-42 reaches high picomolar (> 100 pM) in the extracellular compartment of the rat dentate gyrus, Zn-Aβ1-42 complexes are readily formed and taken up into dentate granule cells, followed by Aβ1-42-induced cognitive decline that is linked with Zn2+ released from intracellular Zn-Aβ1-42 complexes. Aβ1-42-induced intracellular Zn2+ toxicity is accelerated with aging because of age-related increase in extracellular Zn2+. The recent findings suggest that Aβ1-42 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 Aβ1-42-induced pathogenesis leads to preventing the AD development, this review deals with extracellular Zn2+-dependent Aβ1-42 neurotoxicity, which is accelerated with aging.