Preferential Neurodegeneration in the Dentate Gyrus by Amyloid β-Induced Intracellular ZnDysregulation and Its Defense Strategy.

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