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Early-life stress induces the development of Alzheimer's disease pathology via angiopathy

Research Project

Project/Area Number 17K16408
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Psychiatric science
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

TANAKA Tomoko  公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 研究員 (40578986)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアルツハイマー病 / 血管障害 / ミクログリア / 血液脳関門の破綻 / 空間認知記憶の障害 / Aβプラークの形成 / 脳神経疾患 / 脳・神経 / 神経科学 / 生理学
Outline of Final Research Achievements

Alzheimer’s disease (AD) is a major problem. Early-life factors associated with an increased risk for the clinical diagnosis of AD have recently been identified. In the present study, we investigated the involvement of early-life stress in the pathogenesis of AD using heterozygous amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. We found that maternal-separated (MS) Appwt/wt mice showed a vessel impairment in the prefrontal cortex, while MS AppNL-G-F/wt mice additionally showed AD-like phenomenon, and severe vessel impairment. At an early stage, morphological changes were observed in the microglia of the MS AppNL-G-F/wt mice, MS Appwt/wt mice and non-MS AppNL-G-F/wt mice. Microglia activation induced by maternal separation in combination with the APP mutation may impair the vascular system, leading to AD progression. These findings therefore suggest that maternal separation results in the early induction of AD-related pathology via angiopathy.

Academic Significance and Societal Importance of the Research Achievements

発達期ストレスがアルツハイマー病(AD)病態を促進することを実証した我々の結果は、ストレス誘発性のAD発症モデルマウスの作製につながったと考えられる。ADは老年期においても転居や入院などのストレスにより発症や症状悪化が報告されとおり、本モデルマウスはADの病態解明、予防法開発に重要である。また,本研究で初めてADモデルマウスで血管系の変化に先行してミクログリアの変化を同定できた。したがって、ミクログリアは新たな予防のターゲットになりうること、また、その変化は新たなADのバイオマーカーになりうることが示された。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (13 results)

All 2021 2020 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (10 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results)

  • [Journal Article] Early-life stress induces the development of Alzheimer's disease pathology via angiopathy2021

    • Author(s)
      Tanaka Tomoko、Hirai Shinobu、Hosokawa Masato、Saito Takashi、Sakuma Hiroshi、Saido Takaomi、Hasegawa Masato、Okado Haruo
    • Journal Title

      Experimental Neurology

      Volume: 337 Pages: 113552-113552

    • DOI

      10.1016/j.expneurol.2020.113552

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Electrophysiological Effects of Transcranial Direct Current Stimulation on Neural Activity in the Rat Cortex2020

    • Author(s)
      Tomoko Tanaka, Yoshikazu Isomura, Kazuto Kobayashi, Takashi Hanakawa, Satoshi Tanaka, and Manabu Honda
    • Journal Title

      Frontiers in Neuroscience

      Volume: - Pages: 1-10

    • DOI

      10.3389/fnins.2020.00495

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Induction of Alzheimer’s disease pathology by early-life stress2020

    • Author(s)
      Tomoko Tanaka, Shinobu Hirai, Masato Hosokawa, Takashi Saito, Hiroshi Sakuma, Takaomi Saido, Masato Hasegawa, Haruo Okado
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2020.04.27.062729

    • Related Report
      2019 Research-status Report
    • Open Access / Int'l Joint Research
  • [Presentation] Early-life stress facilitates the development of Alzheimer’s disease pathology via angiopathy2020

    • Author(s)
      Tomoko Tanaka, Shinobu Hirai, Masato Hosokawa, Takashi Saito, Takaomi Saido, Masato Hasegawa, Haruo Okado,
    • Organizer
      FENS 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 加齢性脳機能障害における発達期要因の解明2020

    • Author(s)
      田中 智子
    • Organizer
      第36回日本ストレス学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 加齢性脳機能障害における発達期要因の解明2020

    • Author(s)
      田中 智子、平井志伸、細川 雅人、斉藤 貴志、西道 隆臣、佐久間 啓、長谷川 成人、岡戸 晴生
    • Organizer
      第39回日本認知症学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アルツハイマー病研究の最前線:幼若期ストレスの影響と血管障害の関与2020

    • Author(s)
      田中 智子
    • Organizer
      薬物・精神・行動の会セミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Induction of Alzheimer’s disease pathology by early life stress2020

    • Author(s)
      Tomoko Tanaka 1, Shinobu Hirai, Masato Hosokawa, Takashi Saito, Takaomi Saido, Masato Hasegawa, Haruo Okado
    • Organizer
      Federation of European Neuroscience Societies 2020
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Induction of Alzheimer’s disease pathology by early life stress2019

    • Author(s)
      Tomoko Tanaka, Shinobu Hirai, Masato Hosokawa, Takashi Saito, Takaomi Saido, Masato Hasegawa, Haruo Okado
    • Organizer
      6th Congress of Asian College of Neuropsychopohamacology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] The role of RP58 in the maintenance of cognitive function2018

    • Author(s)
      Tomoko Tanaka, Okado Haruo
    • Organizer
      18th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 加齢性機能障害の分子機構の解明2018

    • Author(s)
      田中 智子
    • Organizer
      薬物・精神・行動の会セミナー
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] The role of RP58 in the maintenance of cognitive function2018

    • Author(s)
      Tomoko Tanaka, Okado Haruo
    • Organizer
      Neuro2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 加齢性脳機能障害における発達期要因の解明2018

    • Author(s)
      田中 智子、細川 雅人、斉藤 貴志、西道 隆臣、長谷川 成人、岡戸 晴生
    • Organizer
      第37回日本認知症学会学術集会
    • Related Report
      2018 Research-status Report

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Published: 2017-04-28   Modified: 2022-01-27  

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