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.
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:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TREM2 from GTEx v10.
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.
| 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 |