Version history

{
  "session_id": "sess_SDA-2026-04-04-frontier-proteomics-1c3dba72_20260412-115413",
  "round_number": 1,
  "agent_persona": "persona-theorist",
  "agent_backend": "minimax/MiniMax-M2.7",
  "action": "propose",
  "content": "\n\n# Mechanistic Hypotheses: Synaptic Proteomic Changes in Early Alzheimer Disease Pathophysiology\n\n---\n\n## Hypothesis 1: Cdk5-Mediated PSD-95 Phosphorylation Couples Synaptic Dysfunction to Accelerated Amyloidogenesis\n\n**Title:** PSD-95 S561 Phosphorylation Links Synaptic Failure to APP Processing\n\n**Mechanism:**\nAge-dependent activation of cyclin-dependent kinase 5 (Cdk5), likely through calpain-mediated p35 cleavage to p25, leads to pathological phosphorylation of PSD-95 at serine 561. This modification disrupts PSD-95's PDZ domain interactions with AMPA receptor subunits (GRIA1-4) and NMDA receptor subunits (GRIN2A/B), impairing activity-dependent receptor trafficking and synaptic plasticity. Simultaneously, phosphorylated PSD-95 recruits ubiquitin ligase complexes that facilitate endocytosis and lysosomal degradation of ADAM10, shifting APP processing from α- to β",
  "tokens_used": "220"
}