| First Author | Liu J | Year | 2025 |
| Journal | Immunity | Volume | 58 |
| Issue | 7 | Pages | 1830-1846.e7 |
| PubMed ID | 40373772 | Mgi Jnum | J:369611 |
| Mgi Id | MGI:8220443 | Doi | 10.1016/j.immuni.2025.04.018 |
| Citation | Liu J, et al. (2025) Microglial TMEM119 binds to amyloid-beta to promote its clearance in an Abeta-depositing mouse model of Alzheimer's disease. Immunity 58(7):1830-1846.e7 |
| abstractText | 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 (Abeta) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased AD progression in the 5xFAD mouse model. TMEM119 bound to Abeta 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 Abeta 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. |
