Elucidating mechanisms of microglial activity in Alzheimer's disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21221
• Project/Area Number (Other): 18H06101 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Nagoya University
• Principal Investigator: Sobue Akira 名古屋大学, 環境医学研究所, 特任助教 (80823343)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: アルツハイマー病 / グリア細胞 / 神経炎症

Outline of Final Research Achievements

Suppressor of cytokine signalling (SOCS) proteins act as negative feedback inhibitors, dampening specific cytokine signals to prevent excessive cellular responses and returning the cell to a homeostatic state. In this study, we focused on glial SOCS family genes. Regent X, which is SOCS inhibitor, negatively regulated the expression of inflammatory cytokines in activated microglia in vitro. In addition, chronic X injection ameliorated the cognitive impairments of AppNL-G-F (App-KI) mice. X-treated App-KI mice also showed significantly decrease of amyloid accumulation and activated astrocyte’s markers compared to veh-treated App-KI mice. Moreover, we performed next-generation sequence using RNA isolated from AD precuneus and isolated-microglia from cortex of App-KI mice, and some genes, including the expression of cannabinoid type II receptor (CB2) gene were commonly altered. Astroglial SOCS and microglial CB2 may be a potential therapeutic target for AD.

Free Research Field

病態神経科学

Academic Significance and Societal Importance of the Research Achievements

前臨床試験として用いられてきた従来のADモデルマウスと実際のAD患者における分子病態の乖離などが原因でAD治療候補薬のほとんどが開発中止や第III相試験で有効性を示せていないのが現状であった。本研究はミクログリアにおける神経炎症やAβのクリアランスに着目しており候補因子についてはAD患者脳から抽出済みである。更に、問題となっているヒト-モデル動物間のギャップについては 次世代ADモデルを用いて限りなく臨床に近い実験を実施することが可能である。従って、本研究は、他に類のない独自性の高い課題であり、AD の根治療法薬開発に繋がる十分な実現性をもった研究である。