CYP46A1 Activation as a Therapeutic Strategy to Restore Neuronal Cholesterol Efflux and Reduce Aβ Production
Curated pathway from expert analysis
flowchart TD
A["CYP46A1/Cholesterol 24-Hydroxylase<br/>Neuronal Cholesterol Turnover"]
B["24S-Hydroxycholesterol Output<br/>Cholesterol Efflux Signal"]
C["LXR/ABCA1 Activation<br/>Membrane Lipid Homeostasis"]
D["Amyloidogenic APP Processing Falls<br/>BACE1 Access Reduced"]
E["Synaptic Membrane Fluidity Restored<br/>Receptor Trafficking Stabilized"]
F["Lower A-beta Burden<br/>Neuronal Function Preserved"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for CYP46A1 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 CYP46A1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we apply CRISPR-activation of CYP46A1 in primary cultured neurons derived from 3xTg-AD mice, THEN intracellular cholesterol will decrease by ≥40% and extracellular 24-hydroxycholesterol will increa | Intracellular cholesterol (measured by filipin staining and quantitative fluorescence microscopy) will be reduced by ≥40%, while conditioned medium 24-HC (LC-MS | — no observation — | pending | 0.55 |
| IF we administer a CYP46A1 activator (efavirenz at 10 mg/kg/day, a dose shown to cross the blood-brain barrier) to APP/PS1 transgenic mice for 8 weeks beginning at 6 months of age, THEN hippocampal Aβ | Hippocampal Aβ42 levels will be reduced by ≥30% (measurable by ELISA), with corresponding increase in plasma 24-hydroxycholesterol as a proxy for CYP46A1 activa | — no observation — | pending | 0.65 |