Authors
Jian Meng, Yong Wang, Jinghui Wang, Yiqing Chen, Zihao Zhao, Ziqian Tang, Jing Cao, Xian Zhang, Hong Luo, Huihui Li, Yili Wu, Yingjun Zhao, Weihong Song, Yun-Wu Zhang
Published in
Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 9. Pages e71873.
Abstract
Microglia-mediated clearance of amyloid beta (Aβ) is crucial for mitigating Alzheimer's disease (AD) progression, yet the molecular regulators of microglial phagocytosis remain incompletely understood.
We assessed AD-related phenotypes in 5xFAD mice with microglia-specific deletion of transmembrane protein 59 (TMEM59). Microglial transcriptomic profiling was performed using single-cell RNA sequencing (scRNA-seq). A chaperone-mediated autophagy-targeting chimera (CMATAC) peptide was developed to degrade TMEM59, and its therapeutic efficacy was evaluated.
Microglia-specific TMEM59 ablation attenuated cognitive deficits, Aβ plaque burden, and synapse loss in 5xFAD mice. TMEM59 deficiency reprogrammed disease-associated microglia toward a highly phagocytic state. Mechanistically, TMEM59 deficiency enhanced microglial Aβ phagocytosis in a triggering receptor expressed on myeloid cells 2 (TREM2)-dependent manner, as it stabilized TREM2 protein, whereas loss of TREM2 abolished these protective effects. Treatment with the TMEM59-degrading CMATAC peptide alleviated behavioral deficits and enhanced microglial Aβ phagocytosis in 5xFAD mice.
TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.
PMID:
42786742
Bibliographic data and abstract were imported from PubMed on 25 Sep 2026.
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