Details
- 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
- tokens_used
- 220
Raw fields (1)
- content
# Mechanistic Hypotheses: Synaptic Proteomic Changes in Early Alzheimer Disease Pathophysiology --- ## Hypothesis 1: Cdk5-Mediated PSD-95 Phosphorylation Couples Synaptic Dysfunction to Accelerated Amyloidogenesis **Title:** PSD-95 S561 Phosphorylation Links Synaptic Failure to APP Processing **Mechanism:** Age-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