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Elucidation of the mechanism of exosite and its application to the treatment of Alzheimer's disease

Research Project

Project/Area Number 17K10304
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Psychiatric science
Research InstitutionNational Center for Geriatrics and Gerontology (2018-2019)
Osaka University (2017)

Principal Investigator

Fukumori Akio  国立研究開発法人国立長寿医療研究センター, 認知症先進医療開発センター, 室長 (00788185)

Co-Investigator(Kenkyū-buntansha) 工藤 喬  大阪大学, キャンパスライフ健康支援センター, 教授 (10273632)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsガンマセクレターゼ / アルツハイマー病 / γセクレターゼ / プレセニリン / アミロイド前駆体蛋白 / 非天然アミノ酸 / 光親和性クロスリンク / エクソサイト / ニカストリン / 膜内タンパク分解酵素
Outline of Final Research Achievements

It was discovered that C83, which only differs in amino acid length from C99, which is a precursor of Aβ in Alzheimer's disease, also interacts with the exosite of γ-secretase, but the interacting amino acid residues are different. In addition, we searched for a mutant of the extracellular region of C99 that strongly inhibits γ-secretase cleavage, and observed its binding change to exosite. We also obtained preliminary data suggesting the possibility of developing treatments for Alzheimer's disease.

Academic Significance and Societal Importance of the Research Achievements

認知症、特に患者数の多いADの対策が急務である。新オレンジプラン/認知症大綱が発表され、社会全体で医療、介護やケアにも注力されつつある一方で、治療薬を開発し、病気を根本的に治療することも人々の生活の改善につながり、有効な対策となる。本研究をさらに発展させることで、これまで開発されてきたγセクレターゼ阻害剤の問題点を克服した新規AD治療薬の開発につながり、ADを根本的に治療できる可能性がある。そのことを通じて、認知症患者さんのクオリティーオブライフを改善できる可能性を秘めている。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (8 results)

All 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (2 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Int'l Joint Research] Ludwig-Maximilians University Munich/DZNE -Munich(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Interaction Between APOE Genotype and Diabetes in Cognitive Decline2020

    • Author(s)
      Shinohara M, Tashiro Y, Suzuki K, Fukumori A, Bu G, Sato N.
    • Journal Title

      Alzheimers Dement (Amst) .

      Volume: 12 Pages: 54-63

    • DOI

      10.1016/j.semcdb.2020.03.006

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Interaction between APOE genotype and diabetes in cognitive decline2020

    • Author(s)
      Shinohara Mitsuru、Tashiro Yoshitaka、Suzuki Kaoru、Fukumori Akio、Bu Guojun、Sato Naoyuki
    • Journal Title

      Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

      Volume: 12 Issue: 1 Pages: 2425-2435

    • DOI

      10.1002/dad2.12006

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.2020

    • Author(s)
      Trambauer J, Rodriguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H.
    • Journal Title

      EMBO Rep.

      Volume: 21 Issue: 1

    • DOI

      10.15252/embr.201947996

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis2019

    • Author(s)
      Mentrup Torben、Theodorou Kosta、Cabrera-Cabrera Florencia、Helbig Andreas O.、Happ Kathrin、Gijbels Marion、Gradtke Ann-Christine、Rabe Bjoern、Fukumori Akio、Steiner Harald、Tholey Andreas、Fluhrer Regina、Donners Marjo、Schroeder Bernd
    • Journal Title

      Journal of Experimental Medicine

      Volume: 216 Issue: 4 Pages: 807-830

    • DOI

      10.1084/jem.20171438

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Two Neuropsychiatric Cases Seropositive for Bornavirus Improved by Ribavirin2018

    • Author(s)
      Matsunaga Hidenori、Fukumori Akio、Mori Kohji、Honda Tomoyuki、Uema Takeshi、Tomonaga Keizo
    • Journal Title

      Japanese Journal of Infectious Diseases

      Volume: 71 Issue: 5 Pages: 338-342

    • DOI

      10.7883/yoken.JJID.2017.585

    • NAID

      130007485755

    • ISSN
      1344-6304, 1884-2836
    • Year and Date
      2018-09-30
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] γ-セクレターゼのエクソサイトでの基質認識はAPP C99の細胞外部位の立体構造変化に感受性がある。2018

    • Author(s)
      福森亮雄、 丸山理気、舟本聡、工藤喬、Harald Steiner
    • Organizer
      第37回 日本認知症学会 学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Targeting APP substrate binding of γ-secretase as potential therapeuticapproach for Alzheimer's disease2018

    • Author(s)
      Akio Fukumori
    • Organizer
      Asia Pacific Regional Congress of Biological Psychiatry 2018.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2017-04-28   Modified: 2022-12-28  

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