TREM2-Mediated Spatial Redistribution of Complement Regulators Controls Synapti…

TREM2 signaling controls the spatial distribution of complement regulators CD55 and CD46 on synaptic membranes, determining which synapses are vulnerable to complement-mediated pruning. Under normal conditions, TREM2 activation promotes the expression and clustering of CD55/CD46 at perisomatic inhibitory synapses through DAM pathway signaling, while maintaining low regulator density at distal excitatory synapses. This creates a protective gradient where inhibitory circuits are preserved while allowing physiological pruning of excitatory connections. In TREM2 haploinsufficiency states, this spatial control breaks down—CD55/CD46 redistribution becomes dysregulated, leading to inappropriate complement activation at previously protected inhibitory synapses. The mechanism involves TREM2-dependent regulation of PSD-95 and gephyrin scaffolding proteins, which control CD55/CD46 membrane anchoring. When TREM2 signaling is compromised, PSD-95-mediated competitive inhibition of complement regulators extends aberrantly to inhibitory synapses, while the normal gephyrin-facilitated clustering of CD55/CD46 is lost. This results in widespread synaptic vulnerability and excessive pruning of both excitatory and inhibitory connections. TREM2 agonists (AL002, HFF3760) can restore proper complement regulator distribution by reactivating the DAM pathway and normalizing scaffolding protein function. The decisive experiment involves dual immunofluorescence mapping of CD55/CD46 distribution across synaptic populations in Trem2+/- mice before and after TREM2 agonist treatment, combined with functional assessment of complement C3 deposition patterns.