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Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β1–42-Induced Excess Zn2+ to Functional Zn2+ Deficiency

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Abstract

The role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn2+ dysregulation remains unclear. Here, we report that hippocampal MT induction defends cognitive decline, which was induced by amyloid β1–42 (Aβ1–42)-mediated excess Zn2+ and functional Zn2+ deficiency. Excess increase in intracellular Zn2+, which was induced by local injection of Aβ1–42 into the dentate granule cell layer, attenuated in vivo perforant pathway LTP, while the attenuation was rescued by preinjection of MT inducers into the same region. Intraperitoneal injection of dexamethasone, which increased hippocampal MT proteins and blocked Aβ1–42-mediated Zn2+ uptake, but not Aβ1–42 uptake, into dentate granule cells, also rescued Aβ1–42-induced impairment of memory via attenuated LTP. The present study indicates that hippocampal MT induction blocks rapid excess increase in intracellular Zn2+ in dentate granule cells, which originates in Zn2+ released from Aβ1–42, followed by rescuing Aβ1–42-induced cognitive decline. Furthermore, LTP was vulnerable to Aβ1–42 in the aged dentate gyrus, consistent with enhanced Aβ1–42-mediated Zn2+ uptake into aged dentate granule cells, suggesting that Aβ1–42-induced cognitive decline, which is caused by excess intracellular Zn2+, can more frequently occur along with aging. On the other hand, attenuated LTP under functional Zn2+ deficiency in dentate granule cells was also rescued by MT induction. Hippocampal MT induction may rescue cognitive decline under lack of cellular transient changes in functional Zn2+ concentration, while its induction is an attractive defense strategy against Aβ1–42-induced cognitive decline.

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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

    Atsushi Takeda, Haruna Tamano, Wakana Hashimoto, Shuhei Kobuchi, Hiroki Suzuki, Taku Murakami, Munekazu Tempaku & Yuta Koike

  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. Atsushi Takeda
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  2. Haruna Tamano
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  3. Wakana Hashimoto
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  4. Shuhei Kobuchi
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Correspondence to Atsushi Takeda.

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Takeda, A., Tamano, H., Hashimoto, W. et al. Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β1–42-Induced Excess Zn2+ to Functional Zn2+ Deficiency. Mol Neurobiol 55, 7775–7788 (2018). https://doi.org/10.1007/s12035-018-0948-5

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