Endothelial miR-181c-5p Upregulation Drives Claudin-5 Repression and Paracellular BBB Dysfunction in Preclinical Alzheimer's Disease
🧪 Overview
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.
🧬 Mechanism
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:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CLDN5
No curated PDB or AlphaFold mapping for CLDN5 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CLDN5 (Claudin-5) - regulated by miR-181c-5p from GTEx v10.
💉 Clinical Trials
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.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| 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 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |