Alzheimer’s disease pathogenesis focused on intracellular zn2+ toxicity and its defense strategy

Abstract

The basal levels of intracellular Zn2+ and extracellular Zn2+ are in the range of ~100 pM and ~10 nM, respectively, in the hippocampus. Extracellular Zn2+ dynamics, which serves bidirectionally and involved in cognitive activity and cognitive decline, is modified by extracellular glutamate signaling and the presence of amyloid-β1-42 (Aβ1-42), a causative peptide in Alzheimer’s disease (AD) pathogenesis. When human Aβ1-42 reaches 100–500 pM in the extracellular compartment of the rat hippocampus, Zn-Aβ1-42 complexes are produced and readily taken up into dentate granule cells in a synaptic activity-independent manner. Furthermore, intracellular Zn-Aβ1-42 complexes release Zn2+ followed by intracellular Zn2+ dysregulation. Aβ1-42-mediated intracellular Zn2+ toxicity is accelerated with aging, because extracellular Zn2+ is age-relatedly increased. We have reported that Aβ1-42 released physiologically from neuron terminals disrupts intracellular Zn2+ homeostasis, resulting in age-related cognitive decline and neurodegeneration. Metallothioneins (MTs), zinc-binding proteins can capture Zn2+ released from intracellular Zn-Aβ1-42 complexes and serve for intracellular Zn2+-buffering under acute intracellular Zn2+ dysregulation. Aβ1-42-induced pathogenesis leads the AD development and its defense strategy may prevent the development. This review summarizes extracellular Zn2+-dependent Aβ1-42 neurotoxicity, which is accelerated with aging, and the potential defense strategy against AD.