A modifier model is that APOE4 reactive-state signaling, potentially through NF-kB or mTORC1-linked programs, increases SREBP2 activity even when sterol trafficking is not the sole lesion. This is best treated as an amplifier or combination axis rather than the primary explanation for SCAP-SREBP2 dysregulation.
Curated pathway from expert analysis
flowchart TD
A["APOE4 Reactive Glial State<br/>Astrocyte and Microglia"]
B["NF-kB Pathway Activation<br/>Inflammatory transcription"]
C["mTORC1 Signaling<br/>Nutrient sensing dysregulation"]
D["SCAP Conformational Change<br/>Escort protein activation"]
E["SREBF2/SREBP2 Processing<br/>Sterol regulatory element binding"]
F["Cholesterol Biosynthesis<br/>Gene Upregulation"]
G["Glial Cholesterol<br/>Dyshomeostasis"]
H["Neuronal Lipid<br/>Support Failure"]
A --> B
A --> C
B --> D
C --> D
D --> E
E --> F
F --> G
G --> H
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for SREBF2 yet. Search RCSB →
Median TPM across 13 brain regions for SREBF2 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 SREBF2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF NF-κB signaling is pharmacologically inhibited with IKKβ inhibitor (BAY 11-7082, 5 μM) in APOE4/4 human iPSC-derived astrocytes, THEN SREBP2 nuclear protein levels and downstream target gene expres | SREBP2 activity marker decrease (nuclear translocation and target transcription) | — no observation — | pending | 0.70 |
| IF APOE4/4 and APOE3/3 primary mouse astrocytes (human APOE knock-in) are treated with IL-1β (10 ng/mL) for 6 hours, THEN SREBP2 nuclear localization and cholesterol biosynthesis gene expression will | Genotype-stratified SREBP2 activation difference favoring APOE4 under inflammatory conditions | — no observation — | pending | 0.65 |