TMEM59 以依赖于 TREM2 的方式调控小胶质细胞对淀粉样β蛋白（Aβ）的吞噬作用，并可能成为 Aβ 淀粉样变性的潜在治疗靶点。

Abstract

INTRODUCTION 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. METHODS 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. RESULTS 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. DISCUSSION TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.