[Immune Checkpoint Tim-3 Regulates Microglial Function in Alzheimer's Disease]

Microglia are resident immune cells of the central nervous system and play a central role in the pathogenesis of Alzheimer's disease (AD). Emerging evidence indicates that their functional state critically influences amyloid-β (Aβ) clearance, neuroinflammation, and disease progression. Tim-3, an immune checkpoint molecule, is highly expressed in microglia and functions as a key regulator of microglial homeostasis through the transforming growth factor-β (TGF-β)-Smad2 signaling pathway. Microglia-specific deletion of Tim-3 enhances phagocytic activity. Moreover, microglia-specific Tim-3 deficiency results in reduced Aβ deposition, decreased neurotoxicity, and improved cognitive performance in the 5xFAD mouse model of AD. These effects are not mediated by changes in Aβ production but rather by enhanced microglial clearance and remodeling of Aβ plaques into less toxic forms. Furthermore, single-cell analyses reveal that Tim-3 deficiency promotes a microglial state characterized by increased phagocytic capacity and reduced pro-inflammatory signaling. These findings suggest that Tim-3 acts as a functional checkpoint that limits beneficial microglial responses in AD and that targeting Tim-3 may therefore represent a promising therapeutic strategy for reprogramming microglia and improving disease outcomes.