Preferential Neurodegeneration in the Dentate Gyrus by Amyloid β1-42-Induced Intracellular Zn2+Dysregulation and Its Defense Strategy

Abstract

On the basis of the evidence that rapid intracellular Zn²⁺ dysregulation by amyloid β_1-42 (Aβ_1-42) in the normal hippocampus transiently induces cognitive decline, here we report preferential neurodegeneration in the dentate gyrus by Aβ_1-42-induced intracellular Zn²⁺ dysregulation and its defense strategy. Neurodegeneration was preferentially observed in the dentate granule cell layer in the hippocampus after a single Aβ_1-42 injection into the lateral ventricle but not in the CA1 and CA3 pyramidal cell layers, while intracellular Zn²⁺ dysregulation was extensively observed in the hippocampus in addition to the dentate gyrus. Neurodegeneration in the dentate granule cell layer was rescued after co-injection of extracellular and intracellular Zn²⁺ chelators, i.e., CaEDTA and ZnAF-2DA, respectively. Aβ_1-42-induced cognitive impairment was also rescued by co-injection of CaEDTA and ZnAF-2DA. Pretreatment with dexamethasone, an inducer of metalothioneins, Zn²⁺-binding proteins rescued neurodegeneration in the dentate granule cell layer and cognitive impairment via blocking the intracellular Zn²⁺ dysregulation induced by Aβ_1-42. The present study indicates that intracellular Zn²⁺ dysregulation induced by Aβ_1-42 preferentially causes neurodegeneration in the dentate gyrus, resulting in hippocampus-dependent cognitive decline. It is likely that controlling intracellular Zn²⁺ dysregulation, which is induced by the rapid uptake of Zn-Aβ_1-42 complexes, is a defense strategy for Alzheimer's disease pathogenesis.

Keywords: Alzheimer’s disease; Amyloid β1–42; Dentate gyrus; Extracellular Zn2 +; Metallothionein; Neurodegeneration.