Question
Does the NLRP3 inflammasome enter a locked 'hyperactive' state in senescent astrocytes that perpetuates the senescence-associated inflammasome phenotype (SASP), and does MCC950 (NLRP3 inhibitor) break this lock to reduce neuroinflammation in AD?
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=NLRP3/CASP1/IL1B). Hypothesis: Does the NLRP3 inflammasome enter a locked 'hyperactive' state in senescent astrocytes that perpetuates the senescence-associated inflammasome phenotype (SASP), and does MCC950 (NLRP3 inhibitor) break this lock to reduce neuroinflammation in AD? Success criteria: 1. MCC950 (10mg/kg, 4 weeks) reduces IBA1+/CD68+ microglia by >40% in 5xFAD mice vs vehicle. 2. Senescent astrocyte marker (p16^INK4a) colocalization with NLRP3 decreases by >50% after MCC950. 3. SASP factors (IL-6, CXCL1) in CSF decrease by >35% in MCC950-treated 5xFAD mice. 4. Cognitive performance (Morris water maze) improves by >25% vs vehicle controls.