Extracellular Zn²⁺-Dependent Amyloid-β_1-42 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-β_1-42 (Aβ_1-42), a causative peptide in Alzheimer's disease (AD). When human Aβ_1-42 reaches high picomolar (> 100 pM) in the extracellular compartment of the rat dentate gyrus, Zn-Aβ_1-42 complexes are readily formed and taken up into dentate granule cells, followed by Aβ_1-42-induced cognitive decline that is linked with Zn²⁺ released from intracellular Zn-Aβ_1-42 complexes. Aβ_1-42-induced intracellular Zn²⁺ toxicity is accelerated with aging because of age-related increase in extracellular Zn²⁺. The recent findings suggest that Aβ_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 Aβ_1-42-induced pathogenesis leads to preventing the AD development, this review deals with extracellular Zn²⁺-dependent Aβ_1-42 neurotoxicity, which is accelerated with aging.