Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer's disease.

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) is a homeostatic marker of microglia but has not been fully studied under AD pathological conditions. Here, we observed that amyloid-beta (Aβ) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased AD progression in the 5×FAD mouse model. TMEM119 bound to Aβ oligomers and recruited low-density lipoprotein receptor 1, which in turn degraded TMEM119 itself. Overexpression of TMEM119 in microglia enhanced their phagocytic activity and alleviated cognitive deficits in 5xFAD mice. Administration of the small molecules Kartogenin and SRI-011381, which we found enhanced TMEM119 expression, substantially promoted Aβ clearance and improved cognitive function in AD mice, even during the mid-stage of the disease. These findings identify TMEM119 as a promising therapeutic target for AD.