TREM2 R47H and ABI3 rs616338 are both AD risk loci linked to microglial response, phagocytosis, and cytoskeletal remodeling. The notebook prioritizes them as a convergent module rather than isolated targets. Hypothesis: restoring TREM2-dependent lipid sensing together with ABI3-linked actin remodeling will rescue plaque engagement and debris clearance more robustly than modulating either locus alone in human iPSC-microglia.
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/ABI3 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 human iPSC-derived microglia from AD patients harboring both TREM2 R47H and ABI3 rs616338 risk alleles receive AAV-mediated combinatorial overexpression of TREM2 and ABI3 THEN plaque-associated mic | Combinatorial TREM2+ABI3 overexpression will yield ≥40% greater phagocytic index (amyloid-beta internalization + degradation) and ≥35% increase in plaque-engage | — no observation — | pending | 0.65 |
| IF TREM2-ABI3 double knockout iPSC-microglia receive rescue with TREM2+ABI3 co-expression THEN actin polymerization rates (F-actin/G-actin ratio) and podosome/phagocytic cup dynamics will show ≥50% re | F-actin/G-actin ratio measured by G-actin/F-actin in vivo assay will increase ≥50% in dual-rescue vs double KO, and ≥30% higher than TREM2-only rescue; phagocyt | — no observation — | pending | 0.55 |