GW3965-mediated LXR activation promotes cholesterol efflux via ABCA1/ABCG1, enabling microglia to handle increased neuronal-derived lipid load without inflammatory activation. Amplifies compensatory anti-inflammatory response. Significant systemic toxicity concerns (hepatic steatosis, hypertriglyceridemia) and isoform non-selectivity limit translational potential.
Curated pathway from expert analysis
flowchart TD
A["Target Gene: NR1H3 LXR/NR1H3"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal / Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NR1H3 yet. Search RCSB →
Median TPM across 13 brain regions for NR1H3 (LXRα/NR1H3) 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 NR1H3 (LXRα.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF C57BL/6J mice with established tau pathology (PS19 model) receive daily intraperitoneal GW3965 (10 mg/kg) for 4 weeks, THEN microglial ABCA1/ABCG1 expression will increase ≥2-fold in isolated CD11b | Microglial ABCA1/ABCG1 expression increases ≥2-fold; hippocampal extracellular cholesterol (assessed by LDL receptor expression as proxy) rises by ≥30% indicati | — no observation — | pending | 0.65 |
| IF female 5xFAD mice receive oral GW3965 (15 mg/kg BID) for 8 weeks, THEN hippocampal IBA1+ microglial coverage of amyloid plaques will increase ≥40% and plasma TNF-α will decrease ≥50%, WHILE hepatic | Enhanced microglial peri-plaque coverage (indicating improved lipid handling capacity) and reduced systemic inflammation, but with hepatotoxicity evidenced by h | — no observation — | pending | 0.55 |