ID: hyp-SDA-2026-04-04-frontier-proteomics-1
Hypothesis
Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffolding and Shifts APP Processing
Age-dependent p35-to-p25 cleavage activates Cdk5, which phosphorylates PSD-95 S561, disrupting AMPA/NMDA receptor anchoring and recruiting ubiquitin ligases that degrade ADAM10, thereby redirecting APP processing toward amyloidogenic β-s.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Age-dependent p35-to-p25 cleavage activates Cdk5, which phosphorylates PSD-95 S561, disrupting AMPA/NMDA receptor anchoring and recruiting ubiquitin ligases that degrade ADAM10, thereby redirecting APP processing toward amyloidogenic β-secretase cleavage.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Age-Dependent Calpain Activation<br/>p35 Cleavage to p25"]
B["Cdk5/p25 Hyperactivation<br/>Aberrant Kinase Activity"]
C["PSD-95 DLG4 Ser561 Phosphorylation<br/>Scaffold Protein Destabilized"]
D["AMPA NMDA Receptor Uncoupling<br/>Synaptic Density Protein Loss"]
E["Ubiquitin Ligase Recruitment<br/>ADAM10 Protease Degradation"]
F["APP Processing Redirected<br/>BACE1 over ADAM10 alpha-Secretase"]
G["Amyloid-Beta Generation Increased<br/>Synaptic Plaque Nucleation"]
H["Synapse Loss and AD Progression<br/>Cognitive Decline"]
A --> B
B --> C
C --> D
C --> E
E --> F
F --> G
D --> H
G --> H
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
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Supports
Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.
Supports
Knockdown and inhibition of hippocampal GPR17 attenuates lipopolysaccharide-induced cognitive impairment in mice.
Supports
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PSD-95
No curated PDB or AlphaFold mapping for PSD-95 yet. Search RCSB →
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for PSD-95 (DLG4).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary cortical neurons from APP knock-in mice express p25 (but not p35) via viral transduction for 48-72 hours, THEN PSD-95 S561 phosphorylation will increase, AMPA/NMDA receptor surface expressi | p25 expression will cause ≥50% increase in PSD-95 S561 phosphorylation, ≥30% reduction in surface GluA1 and GluN1, and ≥40% increase in secreted Aβ40/42 compare | — no observation — | pending | 0.78 |
| IF neurons express phospho-mimetic PSD-95 S561D mutant (which cannot be phosphorylated by Cdk5) THEN ADAM10 protein levels and sAPPα secretion will remain stable, whereas wild-type PSD-95 with p25 co- | The S561D mutant will show: (1) no change in ADAM10 levels vs. baseline, (2) sAPPα secretion at baseline levels, (3) no increase in C99/CTFβ, whereas wild-type | — no observation — | pending | 0.72 |
🔮 Falsifiable Predictions (2)
pendingconf 78%
IF primary cortical neurons from APP knock-in mice express p25 (but not p35) via viral transduction for 48-72 hours, THEN PSD-95 S561 phosphorylation will increase, AMPA/NMDA receptor surface expression will decrease, and Aβ40/42 secretion will increase, using murine primary neuronal cultures transd
Predicted outcome: p25 expression will cause ≥50% increase in PSD-95 S561 phosphorylation, ≥30% reduction in surface GluA1 and GluN1, and ≥40% increase in secreted Aβ40/
Falsification: This hypothesis would be disproven if p25 expression does NOT increase PSD-95 S561 phosphorylation, or if Aβ secretion remains unchanged despite elevated p25 levels, indicating Cdk5/p25 acts through a
pendingconf 72%
IF neurons express phospho-mimetic PSD-95 S561D mutant (which cannot be phosphorylated by Cdk5) THEN ADAM10 protein levels and sAPPα secretion will remain stable, whereas wild-type PSD-95 with p25 co-expression will trigger ADAM10 degradation and reduce sAPPα, using human iPSC-derived cortical neuro
Predicted outcome: The S561D mutant will show: (1) no change in ADAM10 levels vs. baseline, (2) sAPPα secretion at baseline levels, (3) no increase in C99/CTFβ, whereas
Falsification: This hypothesis would be disproven if the phospho-mimetic S561D mutant also triggers ADAM10 degradation and reduces sAPPα, demonstrating that S561 phosphorylation is NOT the critical signal for recrui
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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