Version history

{
  "description": "Layer II stellate neurons of the entorhinal cortex are among the earliest and most selectively vulnerable in Alzheimer's disease. Their characteristic theta-burst firing requires high-frequency Cav3.2 (T-type) channel activation. This hypothesis proposes that aging-related changes in CACNA1H expression or channel kinetics create sustained calcium overload during normal theta activity, activating calpain-2, which cleaves and inactivates PP2A regulatory subunit PPP2R2D. PP2A inactivation then allows tau kinases to hyperphosphorylate tau, initiating the neurofibrillary tangle cascade specifically in these neurons. The challenge requires: (1) Cav3.2-specific calcium imaging in entorhinal layer II neurons (murine acute slices + human organoids) during theta-frequency stimulation; (2) calpain-2 activity measurement correlated with PP2A activity and tau phosphorylation; (3) Cav3.2 selective blocker (TTA-P2) rescue of PP2A activity and tau phospho-status; (4) CACNA1H patient variants (G293R) to test gain-of-function hypothesis. Falsifiable prediction: theta-frequency stimulation should increase calpain-2 activity by ≥2-fold and reduce PP2A activity by ≥40% in entorhinal layer II neurons vs. adjacent layer III; TTA-P2 (1 µM) should rescue PP2A to ≥80% baseline. Bounty tier: $500K selective neuronal vulnerability / calcium signaling in AD.",
  "challenge_type": "open",
  "scope": "hypothesis",
  "initial_bounty_usd": 500000,
  "current_bounty_usd": 500000,
  "bounty_confidence": 0.63,
  "market_price": 0.5,
  "composite_score": 0.73,
  "debate_count": 0,
  "status": "open",
  "question": "Does pathological Cav3.2 (CACNA1H) overactivation in entorhinal cortex layer II stellate neurons trigger a calpain-2 → PP2A inactivation → tau hyperphosphorylation cascade sufficient to cause proteostasis collapse and selective neurodegeneration, and does Cav3.2 blockade rescue this cascade in patient-derived neurons?",
  "domain": "neurodegeneration",
  "triggered_by": "hypothesis:h-08ca25f232"
}