Impairment of insulin signaling in Alzheimer's disease and combined therapy with apomorphine and insulin
| Project/Area Number |
17K09302
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General internal medicine(including psychosomatic medicine)
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| Research Institution | Ehime University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山口 浩雄 九州大学, 大学病院, 特任講師 (00701830)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| 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)
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| 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 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(17 results)
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[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
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Journal Title
Neurobiology of Disease
Volume: 137
Pages: 104739-104739
DOI
Related Report
Peer Reviewed / Open Access
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