• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Impairment of insulin signaling in Alzheimer's disease and combined therapy with apomorphine and insulin

Research Project

Project/Area Number 17K09302
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General internal medicine(including psychosomatic medicine)
Research InstitutionEhime University

Principal Investigator

Ohyagi Yasumasa  愛媛大学, 医学系研究科, 教授 (30301336)

Co-Investigator(Kenkyū-buntansha) 山口 浩雄  九州大学, 大学病院, 特任講師 (00701830)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsアルツハイマー病 / 糖尿病 / モデルマウス / アポモルフィン / アミロイドβ蛋白 / 毒性ターン構造 / オリゴマー / リン酸化タウ蛋白 / 毒性ターン / 培養細胞 / インスリンシグナリング / 脳神経疾患 / 痴呆 / 薬理学 / 老化
Outline of Final Research Achievements

Alzheimer’s disease (AD) brain is thought to be in diabetes-like condition. Apomorphine (APO), which we have reported to be a novel drug promoting degradation of amyloid-β protein (Aβ), improves insulin resistance of neurons. In the present study, we induced peripheral diabetic condition in 3xTg-AD mice using the streptozotocin (STZ) injection and high fructose diet, and found an increase in levels of toxic Aβ42 conformer, co-aggregation of Aβ42 and tau protein, impairment of insulin signaling, and activation of microglia in brain. Next, we established an assay system of insulin signaling in cultured N2a cells using western blot and TR-FRET, and confirmed inhibition of insulin signaling by Aβ and recovery of the insulin signaling by APO. Currently, we are investigating possibility of synergistic effects of APO and various anti-diabetic drugs using this assay system.

Academic Significance and Societal Importance of the Research Achievements

ADの治療薬開発では150種類以上の臨床治験が失敗に終わっている。ADの病態について、「脳の糖尿病」説は理解しやすく、また治療戦略として魅力的な仮説である。実際に多数の糖尿病薬がADマウスやAD患者に有効であることが報告されている。APOもインスリンシグナリングを促進すると考えられるが、APOは糖尿病治療薬ではない。従って、糖尿病薬とは別の機序でPI3K-Akt経路を刺激していると考えられ、APOは各種糖尿病薬との併用効果も期待できる。本研究成果は、AD脳内の新たな分子病態をあきらかにし、新規治療法開発のための基盤となる細胞アッセイ系を確立したことである。

Report

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

    (17 results)

All 2020 2019 2018 2017

All Journal Article (6 results) (of which Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (1 results)

  • [Journal Article] Insulin deficiency promotes formation of toxic amyloid-beta42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model.2020

    • Author(s)
      Imamura T, Yanagihara YT, Ohyagi Y, Nakamura N, Iinuma KM, Yamasaki R, Asai H, Maeda M, Murakami K, Ilie K, Kira JI
    • Journal Title

      Neurobiology of Disease

      Volume: 137 Pages: 104739-104739

    • DOI

      10.1016/j.nbd.2020.104739

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insulin signaling as a therapeutic target in Alzheimer's disease: Efficacy of apomorphine.2020

    • Author(s)
      Ohyagi Y, Takei SI
    • Journal Title

      Neurology and Clinical Neuroscience

      Volume: 8 Issue: 3 Pages: 12369-12369

    • DOI

      10.1111/ncn3.12369

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Strategies for Alzheimer's Disease in the View of Diabetes Mellitus2019

    • Author(s)
      Ohyagi y, Miyoshi K, Nakamura N
    • Journal Title

      Adv Exp Med Biol

      Volume: 1128 Pages: 227-248

    • DOI

      10.1007/978-981-13-3540-2_11

    • ISBN
      9789811335396, 9789811335402
    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] 認知症の診断:アルツハイマー病2018

    • Author(s)
      大八木保政
    • Journal Title

      臨床と研究

      Volume: 95 Pages: 233-237

    • Related Report
      2017 Research-status Report
  • [Journal Article] Apomorphine therapy for neuronal insulin resistance in a mouse model of Alzheimer's disease2017

    • Author(s)
      Nakamura N, Ohyagi Y, Imamura T, Yanagihara YT, Iinuma KM, Soejima N, Murai H, Yamasaki R, Kira J
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: 58 Issue: 4 Pages: 1151-1161

    • DOI

      10.3233/jad-160344

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] アルツハイマー型認知症の予防2017

    • Author(s)
      大八木保政
    • Journal Title

      Bio Clinica

      Volume: 32 Pages: 39-43

    • Related Report
      2017 Research-status Report
  • [Presentation] シンポジウム:糖尿病+アルツハイマー病モデルマウスの分子病態と治療薬の開発2019

    • Author(s)
      大八木 保政
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] シンポジウム:アルツハイマー病における脳の糖尿病とアポモルフィン治療の可能性2019

    • Author(s)
      大八木 保政
    • Organizer
      第34回日本老年精神医学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Impairment of insulin signaling by Alzheimer’s amyloid-β protein and protection by apomorphine2019

    • Author(s)
      大八木保政、武井聡子、岡部颯、花岡由理子、井手努、越智雅之、越智博文
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] アルツハイマー病における脳の糖尿病とアポモルフィン治療の可能性2019

    • Author(s)
      大八木保政
    • Organizer
      第34回日本老年精神医学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Apomorphine as a novel drug targeting neuronal insulin signaling in Alzheimer’s disease2019

    • Author(s)
      Ohyagi Y, Takei S, Nakamura N, Imamura T
    • Organizer
      144th Annual Meeting of The American Neurological Association
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 糖尿病+アルツハイマー病モデルマウスの分子病態と治療薬の開発2019

    • Author(s)
      大八木保政
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] アルツハイマー病脳のインスリンシグナリング障害を改善する薬剤評価のための培養細胞アッセイ系の確立2018

    • Author(s)
      武井聡子、大八木保政、越智雅之、越智博文
    • Organizer
      第36回日本神経治療学会学術集会
    • Related Report
      2018 Research-status Report 2017 Research-status Report
  • [Presentation] Glucose intolerance associating with mild cognitive impairment and brain diabetes as a therapeutic target in Alzheimer's disease2017

    • Author(s)
      Ohyagi Y, Ohara M, Igase M, Nakamura T, Imamura T, Yanagihara YT, Kira J, Watanabe A, Fujii N
    • Organizer
      World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Apomorphine as a novel drug for Alzheimer's disease targeting brain diabetes2017

    • Author(s)
      Ohyagi Y, Nakamura N, Imamura T, Watanabe A, Fujii N
    • Organizer
      Neuroscience 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 3xTg-ADマウスの糖インスリン代謝異常はAβ毒性ターン形成を促進する2017

    • Author(s)
      大八木保政、今村友裕、柳原由記
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Book] Diabetes Mellitus: A risk factor for Alzheimer's disease? Chapter: Therapeutic strategies for Alzheimer's disease in the view of diabetes mellitus2018

    • Author(s)
      Ohyagi Y, Nakamura N, Miyoshi K
    • Publisher
      Springer Nature
    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi