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Elucidation of the synapse pathology of Alzheimer's disease with a focus on the receptors which bind amyloid-beta oligomers

Research Project

Project/Area Number 19K07836
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

ARAKI WATARU  東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (60311429)

Co-Investigator(Kenkyū-buntansha) 三條 伸夫  東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト教授 (00343153)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアルツハイマー病 / アミロイドβ / オリゴマー / シナプス / グルタミン酸受容体 / 神経毒性 / 認知症 / 受容体 / アミロイドβタンパク質
Outline of Research at the Start

アミロイドβタンパク質(Aβ)のオリゴマー(AβO)はアルツハイマー病(AD)の初期病態に極めて重要な因子である。AβOはシナプス毒性を持ち、ADにおけるシナプス病態の原因と考えられる。、本研究では、神経細胞およびマウスモデルを用いて、AβOと細胞膜上の受容体との結合に着目した研究を行い、AβOの結合部位の実体を明確化し、そのシナプス毒性の発現メカニズムを明らかにする。

Outline of Final Research Achievements

Soluble assemblies of amyloid-β protein called Aβ oligomers (AβOs) are considered to induce neurotoxicity and synaptotoxicity through binding to certain receptors on the neuronal membrane. However, it remains unclarified which receptors are most critically involved. In this study, we investigated this issue using a model system in which rat primary neurons are exposed to AβOs. We found that AβOs bind to both NMDA receptors containing GluN2B subunits and metabotropic glutamate receptor 1 (mGluR1), which possibly leads to dislocation of both presynaptic and postsynaptic proteins from synapses. Our findings thus clarify part of the molecular mechanisms underlying the synapse pathology of Alzheimer's disease.

Academic Significance and Societal Importance of the Research Achievements

アミロイドβタンパク質(Aβ)は、アルツハイマー病(AD)の脳に線維化し、蓄積するが、むしろ、可溶性のAβの集合体であるAβオリゴマーがシナプス障害などを引き起こす病原因子と考えられている。本研究では、Aβオリゴマーがシナプス障害を引き起こす分子メカニズムを、Aβオリゴマーと候補受容体の結合性の解析から検討した。その結果、GluN2Bサブユニットを含むNMDA受容体と代謝型グルタミン酸受容体1(mGluR1)が、ADのシナプス障害に重要な役割を持つことが明らかとなった。本研究成果は、ADの分子病態解明の一助となるものである。

Report

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

    (8 results)

All 2022 2021 2020 2019

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (3 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] Amyloid-β oligomers interact with NMDA receptors containing GluN2B subunits and metabotropic glutamate receptor 1 in primary cortical neurons: Relevance to the synapse pathology of Alzheimer’s disease2022

    • Author(s)
      Taniguchi Kaori、Yamamoto Fumiko、Amano Akiko、Tamaoka Akira、Sanjo Nobuo、Yokota Takanori、Kametani Fuyuki、Araki Wataru
    • Journal Title

      Neuroscience Research

      Volume: - Pages: 90-98

    • DOI

      10.1016/j.neures.2022.03.001

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia2022

    • Author(s)
      Araki Wataru、Kametani Fuyuki
    • Journal Title

      Antioxidants

      Volume: 11 Issue: 1 Pages: 132-132

    • DOI

      10.3390/antiox11010132

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lemur tail kinase 1 (LMTK1) regulates the endosomal localization of β-secretase BACE12021

    • Author(s)
      Komaki Keisuke、Takano Tetsuya、Sato Yutaka、Asada Akiko、Ikeda Shikito、Yamada Kaoru、Wei Ran、Huo Anni、Fukuchi Aoi、Saito Taro、Ando Kanae、Murayama Shigeo、Araki Wataru、Kametani Fuyuki、Hasegawa Masato、Iwatsubo Takeshi、Tomomura Mineko、Fukuda Mitsunori、Hisanaga Shin-ichi
    • Journal Title

      The Journal of Biochemistry

      Volume: 170 Issue: 6 Pages: 729-738

    • DOI

      10.1093/jb/mvab094

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tyrosol reduces amyloid-β oligomer neurotoxicity and alleviates synaptic, oxidative, and cognitive disturbances in Alzheimer's disease model mice2019

    • Author(s)
      Taniguchi K, Yamamoto F, Arai T, Yang J, Sakai Y, Itoh M, Mamada N, Sekiguchi M, Yamada D, Saitoh A, Kametani F, Tamaoka A, Araki YM, Wada K, Mizusawa H, Araki W
    • Journal Title

      J Alzheimer’s Dis

      Volume: 70 Issue: 3 Pages: 937-952

    • DOI

      10.3233/jad-190098

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] ナノミセル内包型抗Aβオリゴマー抗体によるアルツハイマー病態改善効果2021

    • Author(s)
      天野晶子,三條伸夫,安楽泰孝,中木戸誠,松原悦朗,永田哲也,西田陽一郎,荒木亘,津本浩平,片岡一則,横田隆徳
    • Organizer
      第40回日本認知症学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] アルツハイマー病態と膜ラフト2019

    • Author(s)
      荒木亘
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Amyloid beta-protein oligomers bind to both NMDA receptor and metabotropic glutamate receptor 12019

    • Author(s)
      Araki W, Taniguchi K, Yamamoto F, Arai T, Kametani F, Tamaoka A
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] A composition for prevention and/or treatment for Alzheimer’s disease and/or Alzheimer dementia, and composition for reducing amyloid-beta oligomer neurotoxicity2020

    • Inventor(s)
      Wataru Araki, Jinwei Yang
    • Industrial Property Rights Holder
      Wataru Araki
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
    • Overseas

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

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