Is vulnerability of the dentate gyrus to aging and amyloid-β1–42 neurotoxicity linked with modified extracellular Zn2+ dynamics?

Abstract

The basal levels of extracellular Zn2+ are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn2+ dynamics is critical for cognitive activity and excess influx of extracellular Zn2+ into hippocampal neurons is a known cause of cognitive decline. The dentate gyrus is vulnerable to aging in the hippocampus and affected in the early stage of Alzheimer’s disease (AD). The reasons remain unclear. Neurogenesis-related apoptosis may induce non-specific neuronal depolarization by efflux of intracellular K+ in the dentate gyrus and be markedly increased along with aging. Extracellular Zn2+ influx into dentate granule cells via high K+-induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn2+ dynamics in the dentate gyrus of aged rats is linked with vulnerability to cognitive decline. Amyloid-β1–42 (Aβ1–42) is a causative candidate for AD pathogenesis. When Aβ1–42 concentration reaches picomolar in the extracellular compartment in the dentate gyrus, Zn–Aβ1–42 is formed in the extracellular compartment and rapidly taken up into dentate granule cells, followed by Aβ1–42-induced cognitive decline that is due to Zn2+ released from Aβ1–42, suggesting that dentate granule cells are sensitive to extracellular Zn2+-dependent Aβ1–42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ1–42 neurotoxicity.