Postdoctoral Fellow Institute of Zoology, Chinese Academy of Sciences (CAS) Beijing, China (People's Republic)
Abstract: The progression of Alzheimer's Disease (AD) involves temporal dynamics of microglial activation. Restoring or maintaining microglial homeostasis has emerged as a promising therapeutic strategy to combat AD. Transmembrane protein 119 (TMEM119), a homeostatic marker of microglia, has not been fully studied under AD pathological conditions. In this study, we observed that Aβ induces a dynamic decrease in TMEM119 in microglia, and TMEM119 is associated with the progression of AD in the 5×FAD mouse model. TMEM119 binds to Aβ oligomers and subsequently recruits LRP1, which in turn degrades TMEM119 itself. Overexpression of TMEM119 in microglia enhances their phagocytic activity and alleviates cognitive deficits in 5xFAD mice. Importantly, the administration of small molecules such as Kartogenin (KGN) and SRI-011381 (SRI), which enhance TMEM119 expression, substantially promotes Aβ clearance and improves cognitive function in AD mice, even during the mid-stage of the disease. Therefore, TMEM119 emerges as a promising therapeutic target for AD.
Funding Source: the National Key Research and Development Program of China (2021YFA1101400); the Strategic Priority Research Program of CAS (XDA 0460205); and the Basic Frontier Science Research Program of CAS (ZDBS-LY-SM024).
