Selective induction of a senescence program in adult pericytes is sufficient to impair barrier-supportive trophic signaling, weaken endothelial tight-junction maintenance, and cause durable BBB leak that later contributes to neuronal dysfunction. This is a key causality hypothesis for deciding whether pericyte senescence is a primary lesion or mainly a reactive state.
Curated pathway from expert analysis
flowchart TD
A["Abeta/Tau Stress<br/>DNA Damage Signaling"]
B["CDKN2A/p16 Upregulation<br/>INK4a Locus Activation"]
C["CDK4/6 Inhibition<br/>Cyclin D Complex Blocked"]
D["RB Hypophosphorylation<br/>Cell Cycle Arrest"]
E["Cellular Senescence<br/>Permanent Growth Arrest"]
F["SASP Secretion<br/>IL6/IL8/TNF/MMP Release"]
G["Neuroinflammation<br/>Bystander Neuron Damage"]
H["ARF/p19 Expression<br/>p53 Stabilization"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
B --> H
H -.->|"amplifies"| E
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CDKN2A yet. Search RCSB →
Median TPM across 13 brain regions for CDKN2A, CDKN1A, IL6, CXCL8, TGFB1 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 CDKN2A, CDKN1A, IL6, CXCL8, TGFB1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we selectively induce pericyte senescence in adult mice using pericyte-specific PDGFRβ-CreERT2 to drive CDKN2A overexpression (tamoxifen on P60-P75), THEN we will observe statistically significant | ≥50% increase in brain parenchymal tracer accumulation in pericyte-senescent mice compared to controls | — no observation — | pending | 0.65 |
| IF we pharmacologically prevent pericyte senescence in 5xFAD amyloid model mice by administering senolytic ABT-263 (navitoclax, 50mg/kg/day via drinking water) starting at 6 months, THEN we will obser | ≥40% reduction in IL6 and CXCL8 brain concentrations; ≥30% preservation of pericyte coverage; reversal of 5xFAD cognitive deficits to WT levels | — no observation — | pending | 0.55 |