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

Jing Liu; Zhimeng Wang; Wenwen Liang; Zhenhao Zhang; Yusen Deng; Xiaowei Chen; Zongren Hou; Yuanzhi Xie; Qi Wang; Yuan Li; Chaobo Bai; Da Li; Fan Mo; Huinan Wang; Dongmei Wang; Junliang Yuan; Yukai Wang; Zhao-Qian Teng; Baoyang Hu

doi:10.1016/j.immuni.2025.04.018

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

Immunity. 2025 May 9:S1074-7613(25)00181-5. doi: 10.1016/j.immuni.2025.04.018. Online ahead of print.

Authors

Jing Liu¹, Zhimeng Wang², Wenwen Liang³, Zhenhao Zhang¹, Yusen Deng¹, Xiaowei Chen⁴, Zongren Hou⁵, Yuanzhi Xie¹, Qi Wang³, Yuan Li³, Chaobo Bai³, Da Li¹, Fan Mo¹, Huinan Wang¹, Dongmei Wang¹, Junliang Yuan⁶, Yukai Wang⁷, Zhao-Qian Teng⁸, Baoyang Hu⁹

Affiliations

¹ Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
² School of Pharmaceutical Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing 100191, China.
³ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing 100191, China.
⁴ Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing 100191, China. Electronic address: junliangyuan@bjmu.edu.cn.
⁷ Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: wangyukai@ioz.ac.cn.
⁸ Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: tengzq@ioz.ac.cn.
⁹ Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: byhu@ioz.ac.cn.

PMID: 40373772
DOI: 10.1016/j.immuni.2025.04.018

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) 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.

Keywords: Alzheimer’s disease; LRP1; TMEM119; microglial homeostasis.