Systemic tumors secrete cystatin C which crosses the BBB via LRP1 and engages TREM2 on microglia, shifting neuroinflammatory profile from pro-inflammatory (IL-1β, TNF-α, IL-6) to anti-inflammatory/regulatory (IL-10, TGF-β). This represents the most druggable pharmacology story, though the field's first major TREM2 agonist phase 2 (AL002) missed its clinical primary endpoint despite biomarker engagement. Clinical translation requires biomarker-enriched populations and likely combination therapy with anti-amyloid antibodies.
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/TYROBP 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 5xFAD mice receive bilateral intracerebroventricular infusion of recombinant human cystatin-C (10 μg/day) for 14 days starting at 6 months of age, THEN cortical microglia will show ≥50% increase in | Measurable shift from M1-like to M2-like microglial phenotype quantified by flow cytometry and spatial transcriptomics of cortical tissue; neurobehavioral impro | — no observation — | pending | 0.68 |
| IF cancer patients with solid tumors are stratified by baseline serum cystatin-C into high (top tertile, >2.8 mg/L) vs low (bottom tertile, <1.4 mg/L) groups, THEN patients in the high cystatin-C coho | Inverse correlation between systemic cystatin-C concentration and CNS pro-inflammatory/anti-inflammatory cytokine ratio; detectable cystatin-C in paired CSF sam | — no observation — | pending | 0.62 |