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Elucidation of a neurodegenerative mechanism induced by a new Alzheimer's disease drug target and its inhibition

Research Project

Project/Area Number 26293075
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionFoundation for Biomedical Research and Innovation

Principal Investigator

Hoshi Minako  公益財団法人先端医療振興財団, その他部局等, 研究員 (30374010)

Co-Investigator(Kenkyū-buntansha) 廣明 秀一  名古屋大学, その他の研究科, 教授 (10336589)
大西 隆之  公益財団法人先端医療振興財団, その他部局等, 研究員 (30418959)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2016: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords神経細胞死 / 神経変性疾患 / ナトリウムポンプ / 立体構造 / 新規創薬ターゲット / 脳神経疾患 / シグナル伝達 / 蛋白質 / 構造解析
Outline of Final Research Achievements

Alzheimer's disease is a disorder that causes cognitive decline due to death of mature neurons, but the cause and mechanism of this death of mature neurons had been unknown.
In this work, we showed for the first time that an assembly, a 30-mer of amyloid-β protein, (which we termed amylospheroids) binds to the sodium pump essential for the survival and function of mature neurons and cause death of mature neurons by suppressing the pump function through this binding. In addition, we showed that peptides that bind to amylospheroids inhibit the death of mature neurons by blocking amylospheroids' binding to the sodium pump, and opened up a path to treatment.
We also clarified the tertiary structure of amylospheroids and showed that amylospheroids havd a specific three-dimensional structure.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (25 results)

All 2016 2015 2014 Other

All Int'l Joint Research (1 results) Journal Article (8 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Acknowledgement Compliant: 5 results) Presentation (13 results) (of which Int'l Joint Research: 4 results,  Invited: 11 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] UCLA/University of Illinois at Chicago(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol2016

    • Author(s)
      Shigemitsu, Y., Iwaya, N., Goda, N., Matsuzaki, M., Tenno, T., Narita, A., Hoshi, M.,   *Hiroaki, H.
    • Journal Title

      Analytical Biochemistry

      Volume: 498 Pages: 59-67

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] アルツハイマー病神経細胞死の新たなターゲット分子NA+K+-ATPase ポンプのα3サブユニット2016

    • Author(s)
      星美奈子
    • Journal Title

      医学のあゆみ

      Volume: 258 Pages: 247-248

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol2016

    • Author(s)
      Shigemitsu, Y., Iwaya, N., Goda, N., Matsuzaki, M., Tenno, T., Narita, A., Hoshi, M.
    • Journal Title

      Analytical Biochemistry

      Volume: **

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Aβ(1-42)fibril structure illuminates self-recognition and replication of amyloid in Alzheimers’s disease2015

    • Author(s)
      Xiao, Y., Ma. B., McElheny, D., Parthasarathy, S., Long, F., Hoshi, M., Nussinov, R., and * Ishii, Y.
    • Journal Title

      Nature Str. Mol. Biol.

      Volume: 22 Pages: 499-497

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloidby Solid-state NMR2015

    • Author(s)
      Parthasarathy, S., Inoue, M., Xiao, Y., Matsumura, Y., Nabeshima, Y., Long, F., Hoshi, M., and *Ishii, Y.
    • Journal Title

      J. Amer. Chem. Soc.

      Volume: 137 Pages: 6480-6483

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Na,K-ATPase 3 is a death target of Alzheimer patient amyloid-assembly2015

    • Author(s)
      Ohnishi, T., et al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA.

      Volume: 112

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Yiling Xiao,Buyong Ma,Dan McElheny,Sudhakar Parthasarathy,Fei Long,Minako Hoshi, Ruth Nussinov & *Yoshitaka Ishii2015

    • Author(s)
      Yiling Xiao,Buyong Ma,Dan McElheny,Sudhakar Parthasarathy,Fei Long,Minako Hoshi, Ruth Nussinov and *Yoshitaka Ishii
    • Journal Title

      Nature structural&molecular biology

      Volume: **

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-state NMR2015

    • Author(s)
      Sudhakar Parthasarathy, Masafumi Inoue, Yiling Xiao,Yoshitaka Matsumura,Yo-ichi Nabeshima, Fei Long, Minako Hoshi, and *Yoshitaka Ishii
    • Journal Title

      J. of the American Chemical Society

      Volume: **

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-beta Assembly2016

    • Author(s)
      Hoshi, M.
    • Organizer
      Faculty Lecture
    • Place of Presentation
      KU LEUVEN, Belgium
    • Year and Date
      2016-11-05
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] ATP1A3 as target of beta-amyloid assembly2016

    • Author(s)
      Hoshi, M.
    • Organizer
      5th Symposium on ATP1A3 in Disease
    • Place of Presentation
      UCL Institute of Neurology,London, UK
    • Year and Date
      2016-08-24
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Neurotoxic, high-mass amyloid beta assemblies, amylospheroids, are formed in the Golgi apparatus of neurons that express amyloid precursor proteins with familial Alzheimer mutations2016

    • Author(s)
      Komura,H., Arai,Y., Matsumura,S., Hoshi,M.
    • Organizer
      Gordon Research Conference / Neurobiology of Brain Disorders
    • Place of Presentation
      PGA Catalunya Business and Convention Centre
    • Year and Date
      2016-08-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 球になると毒になる?アルツハイマー病の脳でなぜ神経細胞が死ぬのか?2016

    • Author(s)
      星美奈子
    • Organizer
      Lecture series no.140 京都大学総合博物館
    • Place of Presentation
      京都
    • Year and Date
      2016-06-11
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 新たなアルツハイマー病の発生機構2016

    • Author(s)
      星美奈子
    • Organizer
      バイオファイナンスギルド第14期 第14回セミナー
    • Place of Presentation
      東京
    • Year and Date
      2016-06-10
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病患者脳由来のアミロイドβ凝集体アミロスフェロイドの発見から成熟神経細胞死の分子機構の解明までの道のり2016

    • Author(s)
      星美奈子
    • Organizer
      新潟大学脳神経研究会
    • Place of Presentation
      新潟
    • Year and Date
      2016-02-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病で起こる神経細胞死の新たな分子メカニズムの発見と革新的治療法の開発2016

    • Author(s)
      星美奈子
    • Organizer
      第4回AAA(Academy of Aging and Cardiovascular-Diabetes Research)
    • Place of Presentation
      東京
    • Year and Date
      2016-01-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病患者脳由来のアミロイドβ凝集体アミロスフェロイドの発見から成熟神経細胞の分子機構の解明までの道のり2015

    • Author(s)
      星美奈子
    • Organizer
      構造細胞生物学持論/細胞生物学持論
    • Place of Presentation
      東京
    • Year and Date
      2015-12-17
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-Assembly2015

    • Author(s)
      Hoshi, M.
    • Organizer
      Faculty lecture
    • Place of Presentation
      KU LEUVEN, Belgium
    • Year and Date
      2015-11-05
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-Assembly,2015

    • Author(s)
      Hoshi, M.
    • Organizer
      4th International European Neurodegenerative Diseases & Optogenetics Europe-2015 Meeting
    • Place of Presentation
      University of Cambridge, UK
    • Year and Date
      2015-11-02
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アルツハイマー病で起こる神経細胞死の新たなターゲット分子の発見2015

    • Author(s)
      星美奈子
    • Organizer
      第4回食品薬品生物構造学研究会
    • Place of Presentation
      静岡
    • Year and Date
      2015-10-20
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Calcium-mediated neurotoxicity of high-mass amyloid-beta assembly, amylospheroids (ASPD) to mature hippocampal neurons through activation of voltage-gated calcium channels2014

    • Author(s)
      Ohnishi T, Sasahara T, Komura H, Arai Y, Nishiyama T, Hoshi M
    • Organizer
      Society for Neuroscience 2014
    • Place of Presentation
      Washington, D.C.
    • Year and Date
      2014-11-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトアルツハイマー病(AD)患者由来アミロイドβ凝集体による新たな神経細胞死機構の解明と病態解明に基づくAD新規治療法の研究開発2014

    • Author(s)
      星 美奈子
    • Organizer
      第56回日本老年医学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2014-06-12
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Book] Peptide Self-‐Assembly: Methods and Protocols2016

    • Author(s)
      Yiling Xiao, Dan McElheny, Minako Hoshi, and Yoshitaka Ishii
    • Publisher
      Springer
    • Related Report
      2015 Annual Research Report
  • [Remarks]

    • URL

      http://www.alzforum.org/news/research-news/danger-s-bends-new-structure-av42-fibrils-comes-view

    • Related Report
      2014 Annual Research Report
  • [Remarks]

    • URL

      http://www.kyoto-u.ac.jp/ja/research/research_results/2015/150505_3.html

    • Related Report
      2014 Annual Research Report

URL: 

Published: 2014-04-04   Modified: 2022-01-27  

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