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Drug development for Alzheimer's disease targeting microglial dysfunction

Research Project

Project/Area Number 16K19776
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Psychiatric science
Research InstitutionSapporo Medical University

Principal Investigator

Iwahara Naotoshi  札幌医科大学, 医学部, 助教 (00613085)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアルツハイマー 廟 / 認知症 / ミクログリア / アルツハイマー 病 / アミロイドβ / SOCS3 / 炎症 / アルツハイマー病 / 脳神経疾患 / 痴呆
Outline of Final Research Achievements

We study the molecular mechanism of Alzheimer’s disease (AD), and are trying to develop novel therapy for AD. Accumulation of activated microglia in and around senile plaques has been demonstrated in autopsied brains from AD patients, and considered to modulate amyloid β clearances and inflammation. Our research suggested that microglial activation changes with progression of AD expressing several makers molecule. Activated microglia in the advanced stage of AD model showed higher expression levels of CD14. On the other hands, anti-inflammatory factor, SOCS3, is also up regulated in microglia in advanced AD model. We demonstrated therapeutic effects of mesenchymal stromal cells (MSCs) using AD model mice. We showed that MSC treatment enhanced amyloid beta clearance by microglia.

Academic Significance and Societal Importance of the Research Achievements

今回我々は,ミクログリアによる炎症の抑制ならびにAβの取り込み機構としてSOCS3やTLR4/CD14複合体の役割を解明した.これらの機構を解明することはミクログリアを標的とした新規治療薬を開発する上で重要な知見である.加えて,MSC移植治療が実際にCD14の発現を誘導し,ミクログリアによるAβクリアランスを促進することを示した.MSC移植治療はすでにGVHDや脊髄損傷の治療で臨床応用が始まっており,今回の知見はADに対する臨床応用を検討する上で重要な基礎データとなる.

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2019 2018 2017 2016

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (4 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress2019

    • Author(s)
      Yokokawa Kazuki、Iwahara Naotoshi、Hisahara Shin、Emoto Miho C.、Saito Taro、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Matsushita Takashi、Suzuki Syuuichirou、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: 72 Issue: 3 Pages: 867-884

    • DOI

      10.3233/jad-190817

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease2019

    • Author(s)
      Saito Taro、Hisahara Shin、Iwahara Naotoshi、Emoto Miho C.、Yokokawa Kazuki、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Suzuki Syuuichirou、Matsushita Takashi、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 145 Pages: 20-32

    • DOI

      10.1016/j.freeradbiomed.2019.09.014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway.2019

    • Author(s)
      Fujikura M, Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Manabe T, Matsushita T, Suzuki S, Shimohama S.
    • Journal Title

      J Alzheimers Dis.

      Volume: 68 Issue: 1 Pages: 323-337

    • DOI

      10.3233/jad-180904

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy.2019

    • Author(s)
      Manabe T, Matsumura A, Yokokawa K, Saito T, Fujikura M, Iwahara N, Matsushita T, Suzuki S, Hisahara S, Kawamata J, Suzuki H, Emoto MC, Fujii HG, Shimohama S.
    • Journal Title

      Journal of Alzheimer's disease

      Volume: 67 Issue: 3 Pages: 1079-1087

    • DOI

      10.3233/jad-180985

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice.2017

    • Author(s)
      Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Fujikura M, Manabe T, Suzuki H, Matsushita T, Suzuki S, Shimohama S.
    • Journal Title

      J Alzheimers Dis.

      Volume: 55 Pages: 1235-1247

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] ミクログリアによるAβクリアランスを標的とした治療戦略2018

    • Author(s)
      岩原直敏,下濱俊
    • Organizer
      第37回日本認知症学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Mesenchymal stem cell-conditioned medium promotes amyloid beta phagocytosis by MG6 cells (Mouse microglial cell line).2017

    • Author(s)
      Naotoshi Iwahara
    • Organizer
      World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mesenchymal stem cell-conditioned medium induces microglia into M2 phenotype and promotes amyloid β-phagocytosis2017

    • Author(s)
      Naotoshi Iwahara
    • Organizer
      Society for Neuroscience
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microglial SOCS3 prevents IL6 production in Alzheimer's disease model mice2016

    • Author(s)
      Iwahara, Naotoshi
    • Organizer
      Society for Neuroscience Neuroscience 2016
    • Place of Presentation
      Sandiego
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2021-02-19  

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