| Project/Area Number |
18K19650
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 57:Oral science and related fields
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| Research Institution | Yasuda Women's University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
倪 軍軍 九州大学, 歯学研究院, 助教 (00783953)
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| Project Period (FY) |
2018-06-29 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | ミクログリア / 時計遺伝子 / 炎症性反応 / アルツハイマー病 / ジンジバリス菌 / 網羅的遺伝子解析 / 時計遺伝 / 脳炎症 |
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| Outline of Final Research Achievements |
It is well known that disturbances in clock genes affect almost all patients with Alzheimer’s disease (AD). As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. Pro-inflammatory genes in microglia isolated from APP knock-in mice were significantly higher than those isolated from wild-type mice. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in APP knock-in mice. Therefore, clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation.
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| Academic Significance and Societal Importance of the Research Achievements |
ミクログリアの活性化反応を活動期に規制するゲート機構が存在し、ミクログリア分子時計の制御下にあることが想定された。本研究ではREV-ERBalphaの発現量がミクログリアの活性化反応を規制するゲート機構の実体であることを突き止めた。さらに、REV-ERBalphaによるミクログリアにおける炎症反応は、Abetaオリゴマーにより促進されることが明らかとなった。本研究成果より、ミクログリアの時計遺伝子（特にREV-ERBalpha）を制御することによりアルツハイマー病に伴う過剰な慢性炎症を抑制できる可能性が示唆される。
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