| Project/Area Number |
18K15460
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | アルツハイマー病 / ミクログリア / インフラマソーム / TAK1 / タウオパチー / 神経変性 / NLRP3 / ASC / タウ |
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| Outline of Final Research Achievements |
The pathophysiology of Alzheimer’s disease (AD) is likely strongly influenced by inflammation mediated through microglia. Depletion of microglial TAK1 has been reported to reduce autoimmune inflammation in the central nervous system. This study was aimed to elucidate the involvement of the microglial TAK1 to the progression of tauopathy, a pathological hallmark of AD, as mediated by inflammasome. Transgenic hTau;TAK1ko mice were analyzed for tau pathology, microglial activation, and NLRP3 inflammasome activation by immunohistochemistry. Strong morphological changes were observed in hTau;TAK1ko microglia, whereas microglia in control groups showed minor changes at 4 months. Inflammasome protein NLRP3 and ASC were markedly increased in hTau;TAK1ko mice. Furthermore, hTau;TAK1ko mice had severe ventricle enlargement that indicates cortical atrophy at 12 months. The deficiency of microglial TAK1 led to continuous inflammasome activation through RIPK1 in mouse model of tauopathy.
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| Academic Significance and Societal Importance of the Research Achievements |
ミクログリア特異的TAK1遺伝子除去により、インフラマソーム活性化およびタウ病理の促進が確認された。さらにインフラマソーム活性化が惹起された機序として、TAK1により抑制されていたRIPK1活性が亢進し、疾患関連ミクログリアと呼ばれる特異なサブタイプへの変化に至った経路が示唆された。hTau遺伝子を持たないTAK1ノックアウトマウスではこのような変化に乏しく、hTau遺伝子が存在することで更に神経変性が促進されると推定される。今後はタウの存在とRIPK1活性との関連を解明することで、アルツハイマー病における神経変性の新たな機序を解明するきっかけとなり得ると考えられた。
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