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Amyloid β1–42-Induced Rapid Zn2+ Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia

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Abstract

On the basis of the evidence that amyloid β1–42 (Aβ1–42)-induced Zn2+ influx affects memory acquisition via attenuated long-term potentiation (LTP) induction, here we tested whether Aβ1–42-induced Zn2+ influx affects maintained LTP in freely moving rats, resulting in retrograde amnesia. Both maintained LTP and space memory were impaired by local injection of 250 μM ZnCl2 (2 μl) into the dentate gyrus, while maintained LTP was impaired by injection of either Aβ1–40 or Aβ1–42 (25 μM, 2 μl) into the dentate gyrus. Aβ1–40-induced impairment of maintained LTP was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, but not by co-injection of ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that maintained LTP is impaired by Aβ1–40 via a mechanism that may involve extracellular Zn2+. In contrast, Aβ1–42-induced impairments of maintained LTP and space memory were rescued by co-injection of either CaEDTA or ZnAF-2DA. Intracellular Zn2+ in dentate granule cells was rapidly increased by Aβ1–42 injection into the dentate gyrus, but not by Aβ1–40 injection. The block of Aβ1–42-induced increase in intracellular Zn2+ by pretreatment with dexamethasone, a metallothionein inducer also rescued Aβ1–42-induced impairment of maintained LTP. The present study indicates that Aβ1–42-induced Zn2+ influx into dentate granule cells, which more readily occurs than free Zn2+-induced Zn2+ influx, attenuates maintained LTP followed by retrograde amnesia. It is likely that controlling Aβ1–42-induced intracellular Zn2+ dysregulation is a strategy for defending AD 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, Hiroki Suzuki, Taku Murakami, Hiroaki Fujii & 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. Hiroki Suzuki
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Correspondence to Atsushi Takeda.

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Tamano, H., Suzuki, H., Murakami, T. et al. Amyloid β1–42-Induced Rapid Zn2+ Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia. Mol Neurobiol 56, 5041–5050 (2019). https://doi.org/10.1007/s12035-018-1429-6

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