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Can the age-related decrease in the expression of the novel secretory molecule ILEI be the primary factor in Alzheimer's disease?

Research Project

Project/Area Number 17K17812
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Neurophysiology / General neuroscience
Nerve anatomy/Neuropathology
Research InstitutionShiga University of Medical Science

Principal Investigator

Watanabe Naoki  滋賀医科大学, 神経難病研究センター, 助教 (60769339)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアルツハイマー病 / 遺伝子発現制御 / 脳神経疾患 / 老化 / 神経科学 / ILEI / Amyloid-β / γ-Secretase
Outline of Final Research Achievements

The purpose of this study was to analyze the primary causes of Aβ accumulation in the brain, which is the basic pathophysiology of AD, and to contribute to the development of pre-emptive treatment and diagnosis.
To elucidate the mechanism of down-regulation of ILEI expression, we identified the promoter region of ILEI gene and endogenous transcription factors, suggesting that the down-regulation of ILEI expression in the AD brain is due to the down-regulation of the transcription factors.
To test whether the decreased expression level of ILEI in the brain is a risk factor for the development of AD, we generated ILEI KO and cKO mice by genome editing, and confirmed the disappearance and decrease of ILEI expression in these mice, respectively. These mice were crossed with App(NL-F) and App(NL-G-F) mice, and the analyses are in progress.

Academic Significance and Societal Importance of the Research Achievements

これまで認知症の複数の臨床治験が進められたが、多くは効果不足と副作用から中断を余儀なくされてきた。認知症発症に25年以上先行するとされるAβ蓄積の初期ないし蓄積前からのAβ抑制を行う先制医療の実現のためには、脳内Aβ蓄積の一次的要因を明らかにすることが重要な課題となる。しかし、これまでその知見は極めて乏しく、これが先制医療実現の障壁になっている。本研究による脳内ILEI発現低下機構及びAD発症のリスク因子の検証の成果は、発症前診断法や先制治療法の開発につながるものである。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (26 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (12 results) Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (12 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] CHORI BACPAC Resources Center/National Cancer Institute(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] German Cancer Research Center/Max Planck Institute(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] IGBMC(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Mount Sinai Hospital(カナダ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] CHORI/National Cancer Institute(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] German Cancer Research Center/Max Planck Institute(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] IGBMC(フランス)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Mount Sinai Hospital(カナダ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] CHORI BACPAC Resources Center/National Cancer Institute(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] German Cancer Research Center/Max Planck Institute(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] IGBMC(フランス)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Mount Sinai Hospital(カナダ)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Generation of transgenic cynomolgus monkeys overexpressing the gene for amyloid-β precursor protein2020

    • Author(s)
      Seita Y, Morimura T, Watanabe N, Iwatani C, Tsuchiya H, Nakamura S, Suzuki T, Yanagisawa D, Tsukiyama T, Nakaya M, Okamura E, Muto M, Ema M, Nishimura M, Tooyama I.
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: - Issue: 1 Pages: 45-60

    • DOI

      10.3233/jad-191081

    • NAID

      120006859791

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lipid class composition of membrane and raft fractions from brains of individuals with Alzheimer's disease2019

    • Author(s)
      Kawatsuki A, Morita S-Y, Watanabe N, Hibino E, Mitsuishi Y, Sugi T, Murayama S, Nishimura M.
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 20 Pages: 100704-100704

    • DOI

      10.1016/j.bbrep.2019.100704

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 大脳皮質におけるILEI/FAM3CおよびAβの間質液への分泌様式に関する比較検討2019

    • Author(s)
      中野 将希, 三ツ石 弥千代, 渡邊 直希, 日比野 絵美, 斉藤 貴志, 西道 隆臣, 鈴木 利治, 西村 正樹
    • Organizer
      第38回 日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Synaptic activity-dependent release of presynaptic ilei/FAM3C.2019

    • Author(s)
      中野将希, 三ツ石弥千代, 渡邊直希, 日比野絵美, 斉藤貴志, 西道隆臣, 鈴木利治, 西村正樹
    • Organizer
      AAIC 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Presynaptic ILEI/FAM3C is released in an activity-dependent manner like Aβ exocytosis.2019

    • Author(s)
      中野将希, 三ツ石弥千代, 渡邊直希, 日比野絵美, 斉藤貴志, 西道隆臣, 鈴木利治, 西村正樹
    • Organizer
      Neuro2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] Aβ産生抑制タンパク質ILEI/FAM3Cの転写制御機構の解析2018

    • Author(s)
      渡邊直希, 日比野絵美, 中野将希, 庄司航, 杉拓磨, 西村正樹
    • Organizer
      第37回日本認知症学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Aβ産生抑制タンパク質ILEIの構造および機能の解析2018

    • Author(s)
      日比野絵美, 杉田昌岳, 三ツ石弥千代, 渡邊直希, 中野将希, 杉拓磨, 西村正樹
    • Organizer
      第37回日本認知症学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Structure-based analysis of ILEI/FAM3C activity to inhibit Aβ generation2018

    • Author(s)
      Emi Hibino, Masatake Sugita, Yachiyo Mitsuishi, Naoki Watanabe, Masaki Nakano, Takuma Sugi, Masaki Nishimura
    • Organizer
      第56回日本生物物理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 特異な機序でアミロイドβ産生を抑制するILEI / FAM3Cとアルツハイマー病リスク2018

    • Author(s)
      日比野絵美、渡邊直希、西村正樹
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Aβ産生抑制分子ILEI/FAM3Cの遺伝子転写制御メカニズム2017

    • Author(s)
      渡邊直希, 川月章弘, 日比野絵美, 野村礼, 西村正樹
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 孤発性アルツハイマー病のリスク遺伝子TM2D3の機能解析2017

    • Author(s)
      川月章弘, 渡邊直希, 日比野絵美, 野村礼, 西村正樹
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Aβ産生抑制タンパク質ILEIの構造解析に基づく機能メカニズムの検討2017

    • Author(s)
      日比野絵美, 森田修平, 野村礼, 川月章弘, 渡邊直希, 西村正樹
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 神経系及び非神経系細胞におけるILEI/FAM3C遺伝子の転写制御解析2017

    • Author(s)
      渡邊直希, 庄司航, 川月章弘, 日比野絵美, 野村礼, 西村正樹
    • Organizer
      2017年度生命科学系学会合同年次大会 (ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] Aβ産生抑制タンパク質ILEI/FAM3Cの構造と機能の解析2017

    • Author(s)
      日比野絵美, 森田修平, 杉田昌岳, 渡邊直希, 川月章弘, 野村礼, 西村正樹
    • Organizer
      2017年度生命科学系学会合同年次大会 (ConBio2017)
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2022-02-21  

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