ID: h-32b63761ed
Hypothesis
Fyn-anchored dendritic tau/NMDAR signaling persists after transient Aβ exposure
Aβ drives tau into dendritic spines, where tau binds Fyn and stabilizes a PSD95-NMDAR-associated excitotoxic scaffold.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
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🧪 Overview
Aβ drives tau into dendritic spines, where tau binds Fyn and stabilizes a PSD95-NMDAR-associated excitotoxic scaffold. Once assembled, this complex may persist after Aβ clearance and maintain calcium dysregulation, hyperexcitability, and synaptic degeneration.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["MAPT<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Supports
Dendritic tau mediates Aβ toxicity via Fyn-dependent NMDA receptor signaling, strongly supporting this signaling axis.
Supports
Aβ oligomers induce tau missorting, local calcium rise, and spine loss, consistent with a feed-forward excitotoxic framework.
Supports
Soluble Aβ oligomers drive tau mislocalization to spines and receptor-signaling deficits.
Contradicts
Existing evidence mainly shows that tau is required for Aβ toxicity, not that the tau-Fyn scaffold persists once Aβ is fully absent.
Contradicts
Persistent calcium dysregulation could reflect irreversible spine injury or residual Aβ rather than a self-maintained tau-Fyn complex.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAPT,FYN,DLG4,GRIN2B from GTEx v10.
💉 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 MAPT,FYN,DLG4,GRIN2B.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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Timeline
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF wild‑type mice receive a single intracerebroventricular injection of Aβ1‑42 oligomers (300 pmol) followed by a 7‑day Aβ‑free period, THEN the amount of Fyn‑tau‑PSD95‑NMDAR complex recovered from sy | 2‑fold increase in co‑immunoprecipitated Fyn/tau/PSD95/GRIN2B and a ≥30 % rise in basal calcium fluorescence (GCaMP6f) in CA1 pyramidal neurons. | — no observation — | pending | 0.65 |
| IF human iPSC‑derived cortical neurons are exposed to 200 nM Aβ1‑42 oligomers for 48 h, THEN after a 96‑h Aβ‑free interval the tau Y18 phosphorylation (Fyn site) co‑localized with PSD95 will stay >1.5 | ≥1.5‑fold increase in PLA puncta for pTau(Y18)–PSD95 and ≥40 % decrease in mEPSC frequency. | — no observation — | pending | 0.60 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF wild‑type mice receive a single intracerebroventricular injection of Aβ1‑42 oligomers (300 pmol) followed by a 7‑day Aβ‑free period, THEN the amount of Fyn‑tau‑PSD95‑NMDAR complex recovered from synaptoneurosomes will remain at least 2‑fold higher than in vehicle‑treated controls, AND hippocampal
Predicted outcome: 2‑fold increase in co‑immunoprecipitated Fyn/tau/PSD95/GRIN2B and a ≥30 % rise in basal calcium fluorescence (GCaMP6f) in CA1 pyramidal neurons.
Falsification: Complex abundance returns to ≤1.2‑fold of control AND calcium fluorescence is unchanged (<10 % difference), indicating no persistence.
pendingconf 60%
IF human iPSC‑derived cortical neurons are exposed to 200 nM Aβ1‑42 oligomers for 48 h, THEN after a 96‑h Aβ‑free interval the tau Y18 phosphorylation (Fyn site) co‑localized with PSD95 will stay >1.5‑fold above baseline, AND miniature excitatory postsynaptic current (mEPSC) frequency will remain re
Predicted outcome: ≥1.5‑fold increase in PLA puncta for pTau(Y18)–PSD95 and ≥40 % decrease in mEPSC frequency.
Falsification: pTau(Y18)–PSD95 PLA signal returns to ≤1.2‑fold baseline OR mEPSC frequency is unchanged (<15 % reduction), indicating no persistent signaling.
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _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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