Resolve: Vicious Cycle Hypothesis: Cholinergic Dysfunction Exacerbates Amyloid Pathology

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.

$250

OPEN

Confidence:

30%

Created: 2026-04-27

Linked Targets (2)

CHRNA7 CHRNA7 Protein PDB:7EKK0.39

🧬 View 3D Structure — PDB 7EKK click to expand

BACE1 Beta-secretase 1 PDB:6EQM0.57

🧬 View 3D Structure — PDB 6EQM click to expand

Detected Targets:

BACE1 APP

3D Protein Structure

▶ View 3D structure: BACE1 — PDB 6EQM

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

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Linked Hypotheses (1)

Vicious Cycle Hypothesis: Cholinergic Dysfunction Exacerbates Amyloid Pathology CHRNA7 (α7 nicotinic receptor)0.79