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Preventive strategy against Alzheimer's disease by metallothionein induction

Research Project

Project/Area Number 19H03374
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionUniversity of Shizuoka

Principal Investigator

Takeda Atsushi  静岡県立大学, 薬学部, 客員教授 (90145714)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Keywords亜鉛 / アミロイドβ / アルツハイマー病 / メタロチオネイン / 人参養栄湯 / アミロイド β
Outline of Research at the Start

本研究では、アミロイドβ1-42(Aβ1-42)タンパク質を介した神経細胞内遊離Zn2+の増加は、タウタンパク質を過剰にリン酸化させ、進行性に神経を変性・脱落させてアルツハーマー病の要因となるとの斬新な仮説を実証する。そして、効率的、計画的に海馬メタロチオネイン(MT)合成やアドレナリンβ受容体活性化を誘導し、長期的に神経細胞内でAβ1-42から遊離するZn2+レベルを制御することが進行性神経変性の新規防御・治療戦略となることを実験動物で実証する。

Outline of Final Research Achievements

Human amyloid-β1-42 (Aβ1-42), a causative peptide in Alzheimer’s disease pathogenesis captures extracellular Zn2+ and readily taken up into hippocampal neurons followed by intracellular Zn2+ dysregulation. In contrast, metallothioneins, zinc-binding proteins can capture Zn2+ released from intracellular Zn-Aβ1-42 complexes, resulting in protection of hippocampal neurodegeneration by Aβ1-42-induced Zn2+ toxicity. The present study indicates that pre-administration of Ninjin-yoei-to, a Kampo medicine and dehydroeffusol, a phenanthrene isolated from Juncus effusus prevent Aβ1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aβ1-42. Ninjin-yoei-to and dehydroeffusol, novel inducers of metallothioneins, may protect Aβ1-42-induced pathogenesis in Alzheimer’s disease.

Academic Significance and Societal Importance of the Research Achievements

細胞内亜鉛恒常性に関与するメタロチオネイン(MT)を脳内で誘導合成することにより、Aβ1-42由来のZn2+毒性が軽減し、海馬神経細胞死が阻止できることを実験動物で示すことに成功した。MT誘導合成のために経口投与される人参養栄湯、デヒドロエフソールは自発運動量などに影響を与えない毒性の低い物質である。本研究成果は、アルツハイマー病発症を予防する独創的、かつ斬新的なものであり、超高齢社会である日本でのアルツハイマー病の予防戦略として大いに期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (35 results)

All 2022 2021 2020 2019 2017 Other

All Int'l Joint Research (2 results) Journal Article (24 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 24 results,  Open Access: 1 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 9 results)

  • [Int'l Joint Research] The University of Melbourne(オーストラリア)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Melbourne(オーストラリア)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Paraquat-induced intracellular Zn2+ dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum.2022

    • Author(s)
      Haruna Tamura, Ryusuke Nishio, Nana Saeki, Misa Katahira, Hiroki Morioka, Haruna Tamano, Atsushi Takeda
    • Journal Title

      NeuroToxicology

      Volume: 90 Pages: 136-144

    • DOI

      10.1016/j.neuro.2022.03.010

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Isoproterenol, an adrenergic β receptor agonist, induces metallothionein synthesis followed by canceling amyloid β1-42-induced neurodegeneration2022

    • Author(s)
      Yuya Kawano, Kotaro Tamura, Mako Egawa, Haruna Tamano, Atsushi Takeda
    • Journal Title

      BioMetals

      Volume: in press Issue: 2 Pages: 303-312

    • DOI

      10.1007/s10534-022-00365-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intracellular hydrogen peroxide produced by 6-hydroxydopamine is a trigger for nigral dopaminergic degeneration of rats via rapid influx of extracellular Zn2.2022

    • Author(s)
      Ryusuke Nishio, Hiroki Morioka, Azusa Takeuchi, Nana Saeki, Ryo Furuhata, Misa Katahira, Takato Chinenn, Haruna Tamura, Haruna Tamano, Atsushi Takeda
    • Journal Title

      NeuroToxicology

      Volume: 89 Pages: 1-8

    • DOI

      10.1016/j.neuro.2021.12.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Isoproterenol injected into the basolateral amygdala rescues amyloid β1-42-induced conditioned fear memory deficit via reducing intracellular Zn2+ toxicity.2022

    • Author(s)
      Yudai Ishikawa, Ryusei Itoh, Rin Tsujimoto, Haruna Tamano, Atsushi Takeda
    • Journal Title

      Neurosci Lett

      Volume: 766 Pages: 136353-136353

    • DOI

      10.1016/j.neulet.2021.136353

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid β<sub>1-42</sub>-induced neurodegeneration via intracellular Zn<sup>2+</sup> toxicity in the dentate gyrus2021

    • Author(s)
      Haruna Tamano, Haruna Tokoro, Daichi Murakami, Ryo Furuhata, Satoko Nakajima, Nana Saeki, Misa Katahira, Aoi Shioya, Yukino Tanaka, Mako Egawa, Atsushi Takeda
    • Journal Title

      Experimental Animals

      Volume: 70 Issue: 4 Pages: 514-521

    • DOI

      10.1538/expanim.21-0044

    • NAID

      130008115190

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dehydroeffusol prevents amyloid β1-42-mediated hippocampal neurodegeneration via reducing intracellular Zn2+ toxicity2021

    • Author(s)
      Haruna Tamano, Mako Takiguchi, Nana Saeki, Misa Katahira, Aoi Shioya, Yukino Tanaka, Mako Egawa, Toshiyuki Fukuda, Hiroki Ikeda, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: in press Issue: 8 Pages: 3603-3613

    • DOI

      10.1007/s12035-021-02364-3

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Age-related vulnerability to nigral dopaminergic degeneration in rats via Zn2+-permeable GluR2-lacking AMPA receptor activation2021

    • Author(s)
      Satoko Nakajima, Nana Saeki, Haruna Tamano, Ryusuke Nishio, Misa Katahira, Azusa Takeuchi, Atsushi Takeda
    • Journal Title

      NeuroToxicology

      Volume: 83 Pages: 69-76

    • DOI

      10.1016/j.neuro.2020.12.014

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Retention Period of Amyloid β<sub>1–42</sub> in the Brain Extracellular Fluid as the Toxicological Determinant in Freely Moving Rats2020

    • Author(s)
      Haruna Tamano, Junichi Togo, Yuichi Sato, Aoi Shioya, Munekazu Tempaku, Atsushi Takeda
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 43 Issue: 12 Pages: 1975-1978

    • DOI

      10.1248/bpb.b20-00565

    • NAID

      130007948719

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2020-12-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Zn2+-Dependent Amyloid-β1-42 Neurotoxicity in Alzheimer's Disease Pathogenesis2020

    • Author(s)
      Sato Y, Takiguchi M, Tamano H, Takeda A
    • Journal Title

      Biol Trace Elem Res.

      Volume: in press Issue: 1 Pages: 53-61

    • DOI

      10.1007/s12011-020-02131-w

    • Related Report
      2021 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adrenergic β receptor activation reduces amyloid β1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP2020

    • Author(s)
      Haruna Tamano, Yudai Ishikawa, Aoi Shioya, Ryusei Itoh, Naoya Oneta, Ryota Shimaya, Mako Egawa, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      NeuroToxicology

      Volume: 79 Pages: 177-183

    • DOI

      10.1016/j.neuro.2020.06.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc2020

    • Author(s)
      Zsolt Datki, Zita Galik-Olah, Emese Janosi-Mozes, Viktor Szegedi, Janos Kalman, Akos Gabor Hunya, Livia Fulop, Haruna Tamano, Atsushi Takeda, Paul A Adlard, Ashley I Bush
    • Journal Title

      Mol. Psychiatry

      Volume: 25 Issue: 11 Pages: 2728-2741

    • DOI

      10.1038/s41380-020-0800-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dehydroeffusol rescues amyloid β25-35-induced spatial working memory deficit2020

    • Author(s)
      Toshiyuki Fukuda, Yuichi Sato, Mako Takiguchi, Takahiro Yamamoto, Hiroyasu Murasawa, Akiko Pawlak, Hiroyuki Kobayashi, Haruna Tamano, Atsushi Takeda
    • Journal Title

      lant Foods Hum. Nutr.

      Volume: 75 Issue: 2 Pages: 279-282

    • DOI

      10.1007/s11130-020-00816-0

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preferential neurodegeneration in the dentate gyrus by amyloid β1-42-induced intracellular Zn2+ dysregulation and its defense strategy2020

    • Author(s)
      Haruna Tamano, Mako Takiguchi, Yukino Tanaka, Taku Murakami, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: 57 Issue: 4 Pages: 1875-1888

    • DOI

      10.1007/s12035-019-01853-w

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Age-Dependent Modification of Intracellular Zn<sup>2+</sup> Buffering in the Hippocampus and Its Impact2019

    • Author(s)
      Tamano H, Takeda A
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 7 Pages: 1070-1075

    • DOI

      10.1248/bpb.b18-00631

    • NAID

      130007672145

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-07-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CA1 LTP attenuated by corticosterone is canceled by effusol via rescuing intracellular Zn2+ dysregulation2019

    • Author(s)
      Tamano H, Sato Y, Takiguchi M, Murakami T, Fukuda T, Kawagishi H, Suzuki M, Takeda A
    • Journal Title

      Cell. Mol. Neurobiol.

      Volume: 39 Issue: 7 Pages: 975-983

    • DOI

      10.1007/s10571-019-00693-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Paraquat as an environmental risk factor in Parkinson's disease accelerates age-related degeneration via rapid influx of extracellular Zn2+ into nigral dopaminergic neurons2019

    • Author(s)
      Tamano H, Nishio R, Morioka H, Furuhata R, Komata Y, Takeda A
    • Journal Title

      Mol. Neurobiol.

      Volume: 56 Issue: 11 Pages: 7789-7799

    • DOI

      10.1007/s12035-019-01642-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Zn2+-independently attenuated LTP by human amyloid β1-40 and rat amyloid β1-422019

    • Author(s)
      Haruna Tamano, Mako Takiguchi, Ryota Shimaya, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      Biochem. Bioph. Res. Co.

      Volume: 514 Issue: 3 Pages: 888-892

    • DOI

      10.1016/j.bbrc.2019.05.037

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] In vivo synaptic activity-independent co-uptakes of amyloid β1-42 and Zn2+ into dentate granule cells in the normal brain2019

    • Author(s)
      Haruna Tamano, Naoya Oneta, Aoi Shioya, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      Sci. Rep.

      Volume: 9 Issue: 1 Pages: 6498-6498

    • DOI

      10.1038/s41598-019-43012-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Intake of heated leaf extract of Coriandrum sativum contributes to resistance to oxidative stress via decreases in heavy metal concentrations in the kidney2019

    • Author(s)
      Ryusuke Nishio, Hanuna Tamano, Hiroki Morioka, Azusa Takeuchi and Atsushi Takeda
    • Journal Title

      Plant Foods Hum. Nutr.

      Volume: 74 Issue: 2 Pages: 204-209

    • DOI

      10.1007/s11130-019-00720-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Difference in ability for extracellular Zn2+ influx between human and rat amyloid β1-42 and its significance2019

    • Author(s)
      Haruna Tamano, Hiroki Suzuki, Shuhei Kobuchi, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      NeuroToxicology

      Volume: 72 Pages: 1-5

    • DOI

      10.1016/j.neuro.2019.01.005

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Amyloid β1-42-induced rapid Zn2+ influx into dentate granule cells attenuates maintained LTP followed by retrograde amnesia2019

    • Author(s)
      Haruna Tamano, Hiroki Suzuki, Taku Murakami, Hiroaki Fujii, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: - Issue: 7 Pages: 5041-5050

    • DOI

      10.1007/s12035-018-1429-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Blockade of rapid influx of extracellular Zn2+ into nigral dopaminergic neurons overcomes paraquat-induced Parkinson's disease in rats2019

    • Author(s)
      Haruna Tamano, Hiroki Morioka, Ryusuke Nishio, Azusa Takeuchi, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: - Issue: 6 Pages: 4539-4548

    • DOI

      10.1007/s12035-018-1398-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rapid intracellular Zn2+ dysregulation via membrane corticosteroid receptor activation affects in vivo CA1 LTP2019

    • Author(s)
      Miki Suzuki, Yuichi Sato, Kotaro Tamura, Haruna Tamano, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: 56 Issue: 2 Pages: 1356-1365

    • DOI

      10.1007/s12035-018-1159-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Zn2+ influx into nigral dopaminergic neurons plays a key role for pathogenesis of 6-hydroxydopamine-induced Parkinson's disease in Rats2017

    • Author(s)
      Haruna Tamano, Ryusuke Nishio, Hiroki Morioka, Atsushi Takeda
    • Journal Title

      Mol. Neurobiol.

      Volume: 印刷中 Issue: 1 Pages: 435-443

    • DOI

      10.1007/s12035-018-1075-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] Regulation of progressive neurodegenerative disorders by inducing metallothionein synthesis in the brain2021

    • Author(s)
      Atsushi Takeda
    • Organizer
      第30回金属の関与する生体関連反応シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 亜鉛イオン神経毒性の制御による 進行性神経変性疾患の新規防御戦略2021

    • Author(s)
      武田厚司
    • Organizer
      第48回日本毒性学会学術年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] パーキンソン病の新たな発症機構とパクチーによるその防御2021

    • Author(s)
      武田厚司
    • Organizer
      第22回応用薬理シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] パクチー脳機能改善における科学的実証2021

    • Author(s)
      武田厚司
    • Organizer
      第5回パクチーアカデミー協会学術会議
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 亜鉛イオン神経毒性の制御による進行性神経変性疾患の新規防御戦略2020

    • Author(s)
      武田厚司
    • Organizer
      第93回日本薬理学会
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Invited
  • [Presentation] シナプス亜鉛イオン動態制御破綻による進行性神経変性疾患に向けた革新的防御2020

    • Author(s)
      武田厚司
    • Organizer
      第97回日本生理学会
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Invited
  • [Presentation] New insight of age-related amyloid β1-42-mediated Zn2+ toxicity into Alzheimer’s diseas2019

    • Author(s)
      Atsushi Takeda
    • Organizer
      International Society for Trace Element Researchin Humans XIII
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 微量元素と認知機能2019

    • Author(s)
      武田厚司
    • Organizer
      第30回日本微量元素学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 進行性神経変性疾患における年齢依存的なZn2+毒性とその防御戦略2019

    • Author(s)
      武田厚司
    • Organizer
      第19回日本抗加齢医学会総会
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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