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

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Abstract

On the basis of the evidence that rapid intracellular Zn2+ dysregulation by amyloid β1–42 (Aβ1–42) in the normal hippocampus transiently induces cognitive decline, here we report preferential neurodegeneration in the dentate gyrus by Aβ1–42-induced intracellular Zn2+ dysregulation and its defense strategy. Neurodegeneration was preferentially observed in the dentate granule cell layer in the hippocampus after a single Aβ1–42 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. Aβ1–42-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 Aβ1–42. The present study indicates that intracellular Zn2+ dysregulation induced by Aβ1–42 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-Aβ1–42 complexes, is a defense strategy for Alzheimer’s disease pathogenesis.

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Authors and Affiliations

  1. Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Haruna Tamano, Mako Takiguchi, Yukino Tanaka, Taku Murakami & Atsushi Takeda

  2. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia

    Paul A. Adlard & Ashley I. Bush

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  1. Haruna Tamano
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  2. Mako Takiguchi
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  3. Yukino Tanaka
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Correspondence to Atsushi Takeda.

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Tamano, H., Takiguchi, M., Tanaka, Y. et al. Preferential Neurodegeneration in the Dentate Gyrus by Amyloid β1–42-Induced Intracellular Zn2+Dysregulation and Its Defense Strategy. Mol Neurobiol 57, 1875–1888 (2020). https://doi.org/10.1007/s12035-019-01853-w

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