Circulating miR-181c-5p is upregulated in AD patients and directly targets the CLDN5 3'-UTR, suppressing claudin-5 expression in brain endothelial cells. This leads to tight junction disruption and paracellular leakage. Major weaknesses: non-specific miRNA origin (multiple cell types), no evidence that plasma miRNA crosses BBB to reach endothelial cells, and CLDN5 knockout mice show only mild BBB phenotypes.
Curated pathway from expert analysis
flowchart TD
A["miR-181c-5p<br/>Upregulation"]
B["CLDN5 (Claudin-5)<br/>mRNA Targeting"]
C["Tight Junction<br/>Protein Downregulation"]
D["BBB<br/>Disassembly"]
E["Neurovascular<br/>Uncoupling"]
F["Neuroinflammation<br/>Microglial Activation"]
G["Cognitive<br/>Impairment"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CLDN5 yet. Search RCSB →
Median TPM across 13 brain regions for CLDN5 (Claudin-5) - regulated by miR-181c-5p 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 CLDN5 (Claudin-5) - regulated by miR-181c-5p.
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 miR-181c-5p upregulation drives claudin-5 repression and paracellular BBB dysfunction, then miR-181c-5p levels in endothelial EVs will predict BBB integrity (Qalb, DCE-MRI Ktrans) and cognitive dec | In matched patient samples (n≥80), endothelial EV miR-181c-5p (CD31+CD144+ EVs) inversely correlates with brain CLDN5 mRNA expression (r<-0.45, postmortem tissu | — no observation — | pending | 0.71 |