ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
Caspase-2/3-mediated D421 truncation generates disease-specific aggregation seeds
Proteolytic cleavage at Asp-421 by caspase-2/3 produces aggregation-competent tau C-terminal fragments that are detected in human AD brain but absent in age-matched cognitively normal controls.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Proteolytic cleavage at Asp-421 by caspase-2/3 produces aggregation-competent tau C-terminal fragments that are detected in human AD brain but absent in age-matched cognitively normal controls.
🧬 Mechanism
🔗 Mechanism from KG for CASP2/CASP3
Auto-built from this analysis's top knowledge-graph edges.
graph TD
tau_protein["tau_protein"] -->|undergoes| post_translational_modifi["post_translational_modifications"]
post_translational_modifi_1["post_translational_modifications"] -->|contributes to| pathological_tau["pathological_tau"]
pathological_tau_2["pathological_tau"] -->|causes| neurodegeneration["neurodegeneration"]
CASP2["CASP2"] -->|causes| TAU_Aggregation["TAU Aggregation"]
CASP3["CASP3"] -->|causes| TAU_Aggregation_3["TAU Aggregation"]
EP300["EP300"] -->|causes| K280_acetylated_tau["K280 acetylated tau"]
D421_truncation["D421 truncation"] -->|biomarker for| Alzheimer_s_disease["Alzheimer's_disease"]
K280_acetylation["K280 acetylation"] -->|associated with| Alzheimer_s_disease_4["Alzheimer's_disease"]
CASP2_5["CASP2"] -->|causes| Neurofibrillary_Tangle_Fo["Neurofibrillary Tangle Formation"]
EP300_6["EP300"] -->|regulates| TAU_Acetylation["TAU Acetylation"]
post_translational_modifi_7["post_translational_modifications"] -->|causes| pathological_tau_8["pathological_tau"]
sess_SDA_2026_04_09_gap_d["sess_SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd_20260412-091129"] -->|causal extracted| processed["processed"]
style tau_protein fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi fill:#81c784,stroke:#333,color:#000
style post_translational_modifi_1 fill:#81c784,stroke:#333,color:#000
style pathological_tau fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_2 fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style CASP2 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation fill:#4fc3f7,stroke:#333,color:#000
style CASP3 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation_3 fill:#4fc3f7,stroke:#333,color:#000
style EP300 fill:#ce93d8,stroke:#333,color:#000
style K280_acetylated_tau fill:#4fc3f7,stroke:#333,color:#000
style D421_truncation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease fill:#ef5350,stroke:#333,color:#000
style K280_acetylation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease_4 fill:#ef5350,stroke:#333,color:#000
style CASP2_5 fill:#ce93d8,stroke:#333,color:#000
style Neurofibrillary_Tangle_Fo fill:#4fc3f7,stroke:#333,color:#000
style EP300_6 fill:#ce93d8,stroke:#333,color:#000
style TAU_Acetylation fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi_7 fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_8 fill:#4fc3f7,stroke:#333,color:#000
style sess_SDA_2026_04_09_gap_d fill:#4fc3f7,stroke:#333,color:#000
style processed fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
NRN1 may Modulate Tau Phosphorylation and Neuronal Apoptosis in AD via the PIGU-CASP3 Axis.
Supports
Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias.
Supports
Neuroprotection effect of HSV-1 LAT-derived miR-H2 and miR-H3 associated with Tau and alpha-synuclein downregulation.
Supports
Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.
Supports
Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CASP2
No curated PDB or AlphaFold mapping for CASP2 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 CASP2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
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Volatility
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Events (7d)
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human post-mortem prefrontal cortex (BA9/BA46) tissue from clinically confirmed AD cases (Braak stage V-VI, NIA-AA criteria) is compared to age-matched cognitively normal controls, THEN D421-trunca | ≥3-fold higher concentration of D421 tau fragments in AD vs control tissue (normalized to total tau) | — no observation — | pending | 0.82 |
| IF caspase-2/3 activity is pharmacologically inhibited (using z-VDVAD-fmk or CASP2 siRNA) in iPSC-derived neurons from AD patients carrying MAPT mutations, THEN levels of tau fragments ending at Asp-4 | ≥50% reduction in tau D421 fragments and ≥30% reduction in Sarkowsky-positive aggregate area per cell | — no observation — | pending | 0.75 |
🔮 Falsifiable Predictions (2)
pendingconf 82%
IF human post-mortem prefrontal cortex (BA9/BA46) tissue from clinically confirmed AD cases (Braak stage V-VI, NIA-AA criteria) is compared to age-matched cognitively normal controls, THEN D421-truncated tau fragment concentration will be ≥3-fold higher in AD cases with measurable Thioflavin-S posit
Predicted outcome: ≥3-fold higher concentration of D421 tau fragments in AD vs control tissue (normalized to total tau)
Falsification: Equal or lower D421 fragment levels in AD cases compared to controls (any fold-change <1.0 or p>0.05) would indicate D421 truncation is not disease-specific
pendingconf 75%
IF caspase-2/3 activity is pharmacologically inhibited (using z-VDVAD-fmk or CASP2 siRNA) in iPSC-derived neurons from AD patients carrying MAPT mutations, THEN levels of tau fragments ending at Asp-421 will decrease by ≥50% compared to vehicle-treated controls within 72 hours, with corresponding re
Predicted outcome: ≥50% reduction in tau D421 fragments and ≥30% reduction in Sarkowsky-positive aggregate area per cell
Falsification: No statistically significant reduction in D421 tau fragments (p>0.05) or increased aggregation burden following caspase-2/3 inhibition would disprove the causal link between caspase activity and D421
▸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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