Possible involvement of impaired intrinsic microglial clock in Periodontotis-associated exacerbation of Alzheimer's disease

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K19650
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: Yasuda Women's University
• Principal Investigator: Nakanishi Hiroshi 安田女子大学, 薬学部, 教授 (20155774)
• Co-Investigator(Kenkyū-buntansha): 倪 軍軍 九州大学, 歯学研究院, 助教 (00783953)
• Project Period (FY): 2018-06-29 – 2021-03-31
• 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

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.

Free Research Field

神経化学

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。