Brain Function and Pathophysiology Focused on Zn2+ Dynamics

Abstract

The basal levels of intracellular Zn2+ and extracellular Zn2+ are in the range of ～100 pM and ～10 nM, respectively, in the brain. Extracellular Zn2+ dynamics is involved in both cognitive performance and neurodegeneration. The bidirectional actions are linked with extracellular glutamate and amyloid-β1-42 (Aβ1-42). Intracellular Zn2+ signaling via extracellular glutamate is required for learning and memory, while intracellular Zn2+ dysregulation induces cognitive decline. Furthermore, human Aβ1-42, a causative peptide in Alzheimer's disease pathogenesis captures extracellular Zn2+ and readily taken up into hippocampal neurons followed by intracellular Zn2+ dysregulation. Aβ1-42-mediated intracellular Zn2+ dysregulation is accelerated with aging, because extracellular Zn2+ is age-relatedly increased, resulting in Aβ1-42-induced cognitive decline and neurodegeneration with aging. On the other hand, metallothioneins, zinc-binding proteins can capture Zn2+ released from intracellular Zn-Aβ1-42 complexes and serve for intracellular Zn2+-buffering to maintain intracellular Zn2+ homeostasis. This review summarizes Zn2+ function and its neurotoxicity in the brain, and also the potential defense strategy via metallothioneins against Aβ1-42-induced pathogenesis.