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Extracellular Zn2+-Dependent Amyloid-β1–42 Neurotoxicity in Alzheimer’s Disease Pathogenesis

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Abstract

The basal level of extracellular Zn2+ is in the range of low nanomolar (~ 10 nM) in the hippocampus. However, extracellular Zn2+ dynamics plays a key role for not only cognitive activity but also cognitive decline. Extracellular Zn2+ dynamics is modified by glutamatergic synapse excitation and the presence of amyloid-β1–42 (Aβ1–42), a causative peptide in Alzheimer’s disease (AD). When human Aβ1–42 reaches high picomolar (> 100 pM) in the extracellular compartment of the rat dentate gyrus, Zn-Aβ1–42 complexes are readily formed and taken up into dentate granule cells, followed by Aβ1–42-induced cognitive decline that is linked with Zn2+ released from intracellular Zn-Aβ1–42 complexes. Aβ1–42-induced intracellular Zn2+ toxicity is accelerated with aging because of age-related increase in extracellular Zn2+. The recent findings suggest that Aβ1–42 secreted continuously from neuron terminals causes age-related cognitive decline and neurodegeneration via intracellular Zn2+ dysregulation. On the other hand, metallothioneins (MTs), zinc-binding proteins, quickly serve for intracellular Zn2+-buffering under acute intracellular Zn2+ dysregulation. On the basis of the idea that the defense strategy against Aβ1–42-induced pathogenesis leads to preventing the AD development, this review deals with extracellular Zn2+-dependent Aβ1–42 neurotoxicity, which is accelerated with aging.

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

    Yuichi Sato, Mako Takiguchi, Haruna Tamano & Atsushi Takeda

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  1. Yuichi Sato
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  2. Mako Takiguchi
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  3. Haruna Tamano
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  4. Atsushi Takeda
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Correspondence to Atsushi Takeda.

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Sato, Y., Takiguchi, M., Tamano, H. et al. Extracellular Zn2+-Dependent Amyloid-β1–42 Neurotoxicity in Alzheimer’s Disease Pathogenesis. Biol Trace Elem Res 199, 53–61 (2021). https://doi.org/10.1007/s12011-020-02131-w

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  • DOI: https://doi.org/10.1007/s12011-020-02131-w

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