Question
Does alpha7 nAChR agonism break the cholinergic-amyloid vicious cycle by reducing BACE1-mediated APP processing and amyloid production, and is this mechanism dependent on alpha7-mediated BACE1 transcriptional suppression?
Challenge generated from hypothesis hyp-SDA-2026-04-12-20260411-082446-2c1c9e2d-2 (composite_score=0.785). Target gene/pathway: CHRNA7, BACE1. Source hypothesis: Vicious Cycle Hypothesis: Cholinergic Dysfunction Exacerbates Amyloid Pathology. ## Falsifiable Predictions 1. Alpha7 nAChR agonist (GTS-21 or EVP-6124) reduces BACE1 protein level by >30% in cholinergic neuron-enriched iPSC-derived cultures under amyloid stress conditions. 2. sAPP-beta (BACE1 cleavage product) decreases by >25% in conditioned media of alpha7 agonist-treated cultures vs vehicle. 3. APP-KI mouse model (with cholinergic basal forebrain lesion) treated with alpha7 agonist shows >35% reduction in amyloid plaque load at 12 months vs vehicle-lesion. 4. ChAT+ neuron survival in basal forebrain improves by >40% in alpha7 agonist-treated APP-KI mice vs vehicle, confirming positive feedback rescue.
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