Abstract: Objective To investigate the effects of the T204A variant in triggering receptor expressed on myeloid cells 2(TREM2) on microglial phagocytic function and the activity of the TREM2-DAP12-SYK signaling pathway. Methods Wild-type and mutant constructs were expressed in 293T and HMC3 microglia. Protein expression and localisation were assessed by immunofluorescence and Western blot. Aβ clearance-related capacity was evaluated by measuring residual Aβ levels in the supernatant using ELISA. TREM2-DAP12 interaction was analysed by Co-IP, and SYK/AKT phosphorylation was examined by Western blot. Results This study identified three SNPs in the TREM2 coding region, two of which were located in isoform2 and one in isoform1. None of the three SNPs affected TREM2 expression or localisation. Only T204A significantly reduced residual Aβ levels in the supernatant(P＜0.05), indicating enhanced Aβ clearance-related capacity. Mechanistically, T204A increased TREM2-DAP12 interaction and was associated with elevated SYK phosphorylation. Conclusions TREM2 T204A is a gain-of-function variant that enhances TREM2-DAP12 complex formation and is associated with increased SYK signaling and Aβ clearance in microglia.

Key words: TREM2, microglia, Alzheimer′s disease, neuroimmunity