IRF-1调控DAM功能参与Aβ沉积的机制研究

Aβ斑块持续过量堆积是AD的重要病理机制之一。AD中稳态的小胶质细胞会逐渐转化为疾病相关小胶质细胞（DAM），进而参与Aβ斑块吞噬。但DAM不同表型的关键上游调节因子还有待研究。申请者前期研究发现，转录因子IRF-1在Aβ激活的小胶质细胞中高表达，干扰IRF-1的表达可降低活化的小胶质细胞吞噬Aβ的能力；此外，IRF-1可调控吞噬通路关键基因Tyrobp的表达。据此，申请者提出“IRF-1通过干扰Tyrobp转录过程，调节DAM表型及吞噬能力影响Aβ沉积”。本研究拟以原代小胶质细胞、IRF-1条敲的5xFAD小鼠模型以及AD患者的脑组织标本为载体，通过生物信息学、Nanostring、流式细胞学、TMT-MS等方法，探讨IRF-1通过调节小胶质细胞表型及功能，影响AD中Aβ沉积的作用及机制，为靶向小胶质细胞的AD神经免疫治疗提供新思路。

The continuous excessive accumulation of Aβ plaque is one of the important pathological hallmarks of AD. Microglia transform from homeostatic to disease-associated-microglia (DAM) states in AD and are crucial in phagocytosis of Aβ. However, the key upstream regulators of DAM have not been identified. Our preliminary experiments suggest IRF-1 is overexpressed in Aβ activated microglia. We observed increased Aβ phagocytic capacity in activated microglia and silencing IRF-1 inhibited the LPS-induced augmentation. Moreover, we found IRF-1 regulated the expression of Tyrobp, which is associated with microglia pathogen phagocytosis pathway. Thus, we hypothesize that in AD, loss of IRF-1 would regulate Tyrobp transcription and thus, change the phenotype and phagocytic ability of DAM, which ultimately leads to Aβ deposition. Here, using primary microglia, 5xFAD conditional KO mice and human AD brain slice，we will study the role of IRF-1 in regulating DAM functions and identify the cellular mechanism of IRF-1 underlying the clearance of Aβ. This study will guide development of therapeutic immunomodulatory strategies for AD.