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Involvement of brain pericytes in alpha-synuclein-induced dysfunction of the blood-brain barrier and dopaminergic neurons

Research Project

Project/Area Number 16K08566
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionFukuoka University

Principal Investigator

DOHGU Shinya  福岡大学, 薬学部, 准教授 (60399186)

Co-Investigator(Kenkyū-buntansha) 高田 芙友子  福岡大学, 薬学部, 助教 (70412575)
山内 淳史  福岡大学, 薬学部, 教授 (90341453)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords脳ペリサイト / αシヌクレイン / 血液脳関門 / 炎症性サイトカイン / ドパミン神経 / オートファジー / パーキンソン病 / ドパミン神経細胞 / 神経細胞 / 6-hydroxydopamine
Outline of Final Research Achievements

Parkinson’s disease (PD) is characterized by widespread distribution of aggregated α-synuclein (α-Syn) protein in inclusions known as Lewy bodies and loss of dopaminergic neurons in substantia nigra. α-Syn is secreted from neurons and transferred to neighboring cells. This cell-to-cell transmission of α-Syn is thought to underlie the progress of PD. In addition, disruption of the BBB occurred in the patients with PD. Here, we investigated whether brain pericytes is involved in loss of dopaminergic neurons and BBB disruption in PD.
Brain pericytes inhibited dopaminergic neuronal cell death by decreasing expression of the cleaved caspase-3. Pericytes up-regulate the activity of dopaminergic neurons in healthy condition.
Brain pericytes are sensitive to monomeric α-Syn in terms of the release of various inflammatory cytokines/chemokines and MMP-9 leading to BBB dysfunction. α-Syn-reactive pericytes could contribute to dysfunction of dopaminergic neurons and BBB in patient with PD.

Academic Significance and Societal Importance of the Research Achievements

血液脳関門機能低下と認知機能障害が相関することが明らかにされており、αシヌクレインによって誘発される血液脳関門機能破綻が認知機能障害誘発に繋がるかもしれない。さらに、αシヌクレイン単量体はペリサイトのドパミン神経機能亢進作用の抑制因子でもある。一方で、脳ペリサイトはαシヌクレインを細胞内へ取り込み、分解することで、脳内での過剰なαシヌクレイン蓄積を抑制しているかもしれない。従って、脳ペリサイトの機能低下はαシヌクレイン病態の加速因子となり得る。今後in vivoでの検討が必要であるが、ペリサイトがαシヌクレイン病態を解明する鍵になる可能性がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2019 2018 2017 2016

All Journal Article (2 results) (of which Peer Reviewed: 1 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Monomeric α-synuclein induces blood-brain barrier dysfunction through activated brain pericytes releasing inflammatory mediators in vitro.2019

    • Author(s)
      Dohgu S, Takata F, Matsumoto J, Kimura I, Yamauchi A, Kataoka Y.
    • Journal Title

      Microvasc Res.

      Volume: 124 Pages: 61-66

    • DOI

      10.1016/j.mvr.2019.03.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ペリサイトを基軸としたαシヌクレインによる血液脳関門および神経細胞の連動的障害2019

    • Author(s)
      道具伸也
    • Journal Title

      メディカル・サイエンス・ダイジェスト

      Volume: 45 Pages: 18-21

    • Related Report
      2018 Annual Research Report
  • [Presentation] 脳ペリサイトにおけるαシヌクレインの取り込みおよび分解機構2019

    • Author(s)
      道具伸也、矢野瑞紀、横谷みき、高田芙友子、松本純一、木村郁哉、山内淳史、片岡泰文
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Role of Brain Pericytes in Parkinson’s disease2019

    • Author(s)
      Shinya Dohgu
    • Organizer
      1st Mini-symposium on the blood-brain barrier from basic to clinical research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 脳ペリサイトによるα-シヌクレインの細胞内取り込み機構2018

    • Author(s)
      矢野瑞紀、道具伸也、横谷みき、高田芙友子、松本純一、木村郁哉、山内淳史、片岡泰文
    • Organizer
      第71回日本薬理学会西南部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] In response to monomeric α-synuclein, brain pericytes release inflammatory cytokines to impair brain endothelial barrier2018

    • Author(s)
      Shinya Dohgu, Fuyuko Takata, Junichi Matsumoto, Ikuya Kimura, Atsushi Yamauchi, Yasufumi Kataoka.
    • Organizer
      18th World congress of basic and clinical pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脳ペリサイトは6-OHDA誘発性ドパミン神経細胞傷害を防御する2017

    • Author(s)
      有留尚孝、道具伸也、牛尾誠幸、藤田侑里、木村郁哉、高田芙友子、片岡泰文、山内淳史
    • Organizer
      七隈アルツハイマー病・パーキンソン病研究会
    • Place of Presentation
      BiVi福岡 6F 会議室1-3
    • Year and Date
      2017-04-08
    • Related Report
      2016 Research-status Report
  • [Presentation] 脳ペリサイトは6-OHDA誘発性ドパミン神経細胞傷害を防御する2017

    • Author(s)
      有留尚孝、道具伸也、牛尾誠幸、藤田侑里、木村郁哉、高田芙友子、片岡泰文、山内淳史
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎ブリックホール、長崎新聞文化ホール アストピア
    • Year and Date
      2017-03-15
    • Related Report
      2016 Research-status Report
  • [Presentation] α-Synuclein-reactive pericytes contribute to the blood-brain barrier dysfunction through the release of inflammatory cytokines in vitro.2017

    • Author(s)
      Shinya Dohgu, Fuyuko Takata, Junichi Matsumoto, Ikuya Kimura, Atsushi Yamauchi, Yasufumi Kataoka
    • Organizer
      Cerebral Vascular Biology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脳ペリサイトによる6-OHDA誘発性ドパミン神経細胞傷害の保護機構2016

    • Author(s)
      有留尚孝、道具伸也、牛尾誠幸、藤田侑里、木村郁哉、片岡泰文、山内淳史
    • Organizer
      第69回日本薬理学会西南部会
    • Place of Presentation
      松山大学
    • Year and Date
      2016-11-26
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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