Development of therapeutic strategy for Alzheimer's disease via M2 microglia

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07389
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Daiichi University, College of Pharmaceutical Sciences (2020); University of Toyama (2018-2019)
• Principal Investigator: Kuboyama Tomoharu 第一薬科大学, 薬学部, 准教授 (10415151)
• Co-Investigator(Kenkyū-buntansha): 東田 千尋 富山大学, 学術研究部薬学・和漢系, 教授 (10272931)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: アルツハイマー病 / マイクログリア / 軸索 / HDAC3

Outline of Final Research Achievements

Amyloid β (Aβ) skews microglia to M1 phenotype and induces inflammation and neurodegeneration. On the other hand, another type of microglia, M2, shows anti-inflammatory and neurotrophic effects. We previously clarified that HDAC3 inhibition induced predominance of M2 microglia and axonal growth. Therefore, this study aimed to clarify that HDAC3 inhibition skewed to M2 microglia and restored memory function in in vitro and in vivo Alzheimer’s disease models. As a result, RGFP966 skewed microglia from M1 to M2 in Aβ-treated cultured microglia. RGFP966 promoted secretion of factor A, which normalized morphology of axonal endings after Aβ treatment in cultured neurons. RGFP966 decreased degenerated axons and improved novel object recognition memory in a transgenic model of Alzheimer’s disease, 5XFAD mice. These results suggest that HDAC3 inhibition increased predominance of M2 microglia, recovered axonal degeneration, and ameliorated memory deficit in 5XFAD mice.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病が難治性である原因は、発症時には既に脳内に多くのアミロイドβが沈着し、神経回路網の破綻が生じているためだと考えられている。本研究成果は、HDAC3阻害剤RGFP966が、変性軸索正常化因子・因子Aを分泌し、変性した脳内の神経回路網を再構築することにより、抗アルツハイマー病作用を示したと考えられる。本研究は新たなアルツハイマー病治療法の開発に繋がるものであると考える。