Question
Can selective modulation of the TREM2-C3 axis (TREM2 agonism + C3 inhibition) simultaneously restore microglial phagocytosis and block complement-mediated synaptic pruning in AD?
Falsifiable prediction from high-scoring hypothesis (score=0.726, gene=TREM2 and C3). Hypothesis: Can selective modulation of the TREM2-C3 axis (TREM2 agonism + C3 inhibition) simultaneously restore microglial phagocytosis and block complement-mediated synaptic pruning in AD? Success criteria: 1. TREM2 agonist (AL002c) + C3 inhibitor (avacopan) co-treatment increases amyloid-beta uptake by >50% vs single agent. 2. C3a generation (ELISA) is reduced by >60% in activated microglia co-treated vs TREM2 agonist alone. 3. Synaptic marker (PSD95) intensity is preserved (>85% vs sham) in 5xFAD mice co-treated vs >40% loss in vehicle. 4. Cognitive function (Morris water maze) improves by >25% in co-treatment group vs single-agent controls.