Hypothesis: TREM2 lipid handling modulates microglial lysosomal stress in early AD.
Curated pathway from expert analysis
flowchart TD A["Amyloid-beta accumulation"] B["TREM2 activation"] C["SYK pathway engagement"] D["Microglial lipid handling"] E["Lysosomal stress response"] F["Microglial activation state"] G["Alzheimer's disease progression"] A --> B B --> C B --> D D --> E C --> F E --> F F --> G A["Amyloid-beta accumulation"]:::red B["TREM2 activation"]:::blue C["SYK pathway engagement"]:::blue D["Microglial lipid handling"]:::blue E["Lysosomal stress response"]:::red F["Microglial activation state"]:::blue G["Alzheimer's disease progression"]:::red classDef red fill:#ef5350,stroke:#b71c1c,color:#ffffff classDef blue fill:#4fc3f7,stroke:#0277bd,color:#000000 classDef green fill:#81c784,stroke:#2e7d32,color:#000000 classDef yellow fill:#ffd54f,stroke:#f9a825,color:#000000
No 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.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF TREM2 lipid-sensing function is pharmacologically enhanced using an agonistic antibody (e.g., AL002c) in 5xFAD mice during early disease stage (3-4 months), THEN microglial lysosomal stress markers | At least 30% reduction in composite lysosomal stress score (LAMP1 intensity + cathepsin D activity + lipid droplet number) in entorhinal cortex and hippocampus | — no observation — | pending | 0.65 |
| IF microglia are exposed to a lipid-rich environment (100 μg/mL oxidized LDL) ex vivo, THEN TREM2-deficient iPSC-derived microglia will exhibit at least 50% greater lysosomal membrane permeabilization | Galectin-3 puncta count ≥50% higher in TREM2 knockout iPSC-microglia vs. isogenic controls following oxLDL exposure, with corresponding ≥40% increase in ROS pro | — no observation — | pending | 0.58 |