TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis

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.