ID: h-a4fca7bb87
Hypothesis
Peri-plaque tau seeding restraint via TREM2-competent microglia
TREM2-activated microglia limit neuritic plaque tau spread around amyloid plaques through enhanced phagocytosis of extracellular tau seeds, consistent with Leyns et al.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
TREM2-activated microglia limit neuritic plaque tau spread around amyloid plaques through enhanced phagocytosis of extracellular tau seeds, consistent with Leyns et al. This is the best tau-facing survivor but applies only in mixed amyloid-tau biology, not pure tauopathy. The Li et al. 2026 Cell paper showed no effect on tau in rTg4510 mice (pure tauopathy), which is consistent with this hypothesis.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Amyloid-beta Plaques<br/>Phospholipid Ligands"]
B["TREM2 Receptor<br/>Ligand Binding"]
C["TYROBP/DAP12<br/>ITAM Phosphorylation"]
D["SYK Kinase<br/>Activation"]
E["PLCG2<br/>IP3 + DAG Generation"]
F["Ca2+ Release<br/>Cytoskeletal Remodeling"]
G["Microglial Phagocytosis<br/>Plaque Compaction"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Contradicts
TREM2 deficiency can also reduce tau seeding propagation in specific contexts
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TREM2
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TREM2 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 TREM2.
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 we administer a TREM2-agonist antibody (LECN-147 or similar) to 5-month-old 5xFAD x P301S mice for 8 weeks, THEN plasma p-tau217 concentrations will decrease by ≥30% relative to isotype-control-tre | ≥30% reduction in plasma p-tau217 levels | — no observation — | pending | 0.65 |
| IF we conditionally delete TREM2 in microglia of 5xFAD x P301S mice at 6 months of age using Cx3cr1-CreERT2;TREM2-flox crosses, THEN the spatial spread of AT8-positive dystrophic neurites will increas | ≥40% increase in tau pathology spread radius from amyloid cores | — no observation — | pending | 0.70 |
🔮 Falsifiable Predictions (2)
pendingconf 70%
IF we conditionally delete TREM2 in microglia of 5xFAD x P301S mice at 6 months of age using Cx3cr1-CreERT2;TREM2-flox crosses, THEN the spatial spread of AT8-positive dystrophic neurites will increase by ≥40% within 100μm of Thioflavin-S-positive amyloid cores within 3 months post-deletion.
Predicted outcome: ≥40% increase in tau pathology spread radius from amyloid cores
Falsification: No significant difference in tau spread distance (p>0.05) or even reduced spread in TREM2-deleted mice would disprove the hypothesis
pendingconf 65%
IF we administer a TREM2-agonist antibody (LECN-147 or similar) to 5-month-old 5xFAD x P301S mice for 8 weeks, THEN plasma p-tau217 concentrations will decrease by ≥30% relative to isotype-control-treated littermates.
Predicted outcome: ≥30% reduction in plasma p-tau217 levels
Falsification: No change or increase in plasma p-tau217 despite TREM2 activation would indicate either (a) TREM2 does not reduce tau seeding in vivo or (b) peripheral biomarkers do not capture CNS tau spread
▸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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