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2023 Fiscal Year Final Research Report

Elucidation of amyloid-tau association and development of new therapeutic methods based on analysis of microglia RIPK1

Research Project

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Project/Area Number 21K07420
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionYokohama City University

Principal Investigator

KATSUMOTO Atsuko  横浜市立大学, 医学研究科, 客員講師 (20806161)

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)
Project Period (FY) 2021-04-01 – 2024-03-31
Keywordsmicroglia / 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.

Free Research Field

神経変性疾患

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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Published: 2025-01-30  

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