2023 Fiscal Year Final Research Report
Elucidation of amyloid-tau association and development of new therapeutic methods based on analysis of microglia RIPK1
Project/Area Number |
21K07420
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Yokohama City University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
竹内 英之 横浜市立大学, 医学研究科, 客員教授 (30362213)
田中 章景 横浜市立大学, 医学研究科, 教授 (30378012)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Keywords | microglia / tau / amyloid-beta / RIPK1 |
Outline of Final Research Achievements |
TGF-β activated kinase 1 (TAK1), a key mediator in the TNF inflammatory signaling pathway, is activated by many inflammatory signals but also exerts anti-cell death processes. We examined how TAK1 suppresses the function of RIPK1 and acts on neuroinflammation in an AD model with tau accumulation and amyloid β accumulation. In a tau accumulation model, we demonstrated that the deficiency of microglial TAK1 induced continuous inflammasome activation accompanied by enhanced RIPK1 expression, exacerbating tauopathy in the hTau mice. On the other hand, in the amyloid accumulation model, TAK1 knockout suppressed microglial activation and reduced amyloid deposition, and no difference was observed in RIPK1 expression. Microglial TAK1 deficiency yielded opposite results in the mouse model of tauopathy and amyloid. The above results suggested that the RIPK activation pathway by TAK1 differs depending on the background pathology.
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Free Research Field |
神経変性疾患
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Academic Significance and Societal Importance of the Research Achievements |
神経炎症に対するミクログリア特異的TAK1遺伝子除去効果は、タウ蓄積モデルとアミロイドβ蓄積モデルで全く異なっていた。背景病理によってTAK1によるRIPK活性化経路が異なることが示唆され、抗Aβ薬のみによるAD治療で効果が限定されてしまう現象を一部説明し得ると考えられる。
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