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

On the basis of the evidence that rapid intracellular Zn2+ dysregulation by amyloid beta(1-42) (A beta(1-42)) in the normal hippocampus transiently induces cognitive decline, here we report preferential neurodegeneration in the dentate gyrus by A beta(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 A beta(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. A beta(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 A beta(1-42). The present study indicates that intracellular Zn2+ dysregulation induced by A beta(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-A beta(1-42) complexes, is a defense strategy for Alzheimer's disease pathogenesis.