Cystatin-C-activated TREM2 microglia reduce tau pathology through enhanced phagocytosis of extracellular tau seeds. Critical limitation: microglial phagocytosis can only address extracellular seeds, not intracellular neurofibrillary tangles. This severely limits therapeutic scope to disease prevention rather than modification of established pathology.
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/Syk/PLCγ2 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 TREM2 is pharmacologically activated (via systemic administration of a TREM2 agonistic antibody at 10mg/kg twice weekly for 4 weeks) in 3-month-old P301S tauopathy mice, THEN extracellular tau seed | ≥50% reduction in extracellular tau seeds (seed-competent species detectable by RT-QuIC) within 4 weeks of TREM2 activation | — no observation — | pending | 0.60 |
| IF TREM2 is activated (via cross-linked agonistic antibody) in primary microglia co-cultured with pre-formed tau fibrils, THEN intracellular aggregated tau will NOT decrease below baseline after 72 ho | No reduction in intracellular tau aggregates (<5% change) despite ≥2-fold enhancement of extracellular tau phagocytosis | — no observation — | pending | 0.55 |