Neuroinflammation triggers astrocyte and microglial MMP-9 activation, which proteolytically cleaves claudin-5, the principal tight junction protein. Claudin-5 fragmentation results in immediate BBB hyperpermeability. However, MMP-9 is not brain-specific (elevated in systemic inflammation), multiple MMPs can cleave claudin-5, and claudin-5 cleavage product detection is technically infeasible with current assays.
Curated pathway from expert analysis
flowchart TD
A["Neuroinflammation"]
B["Astrocyte / Microglial<br/>MMP-9 Activation"]
C["Claudin-5<br/>Proteolytic Cleavage"]
D["Tight Junction<br/>Disruption"]
E["BBB<br/>Breakdown"]
F["Neurovascular<br/>Uncoupling"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MMP9 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 MMP9.
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 astrocyte-specific MMP-9 is genetically ablated (GFAP-Cre;MMP-9flox/flox) in an LPS-induced neuroinflammation model, THEN the magnitude of BBB permeability increase will not differ significantly fr | No significant difference in BBB permeability attenuation across cellular source of MMP-9 ablation | — no observation — | pending | 0.35 |
| IF selective MMP-9 inhibition (SB-3CT, 50 mg/kg i.p., 2x daily) is administered to 6-month-old 5xFAD mice for 4 weeks starting at disease onset, THEN brain Evans blue extravasation will decrease by ≥4 | Evans blue extravasation reduced ≥40%; claudin-5 full-length protein increased ≥30% | — no observation — | pending | 0.45 |