LRP1 at brain microvascular endothelium mediates Aβ export from CNS to periphery. AD-associated inflammation activates ADAM10/17-mediated proteolytic shedding of LRP1's extracellular domain (sLRP1), reducing endothelial Aβ clearance capacity. However, LRP1 is ubiquitously expressed (liver, lung, macrophages), and peripheral sources dominate plasma sLRP1, making brain-specific interpretation unreliable.
Curated pathway from expert analysis
flowchart TD
A["AD-associated<br/>Inflammation"]
B["ADAM10/17-mediated<br/>LRP1 Shedding"]
C["sLRP1<br/>Fragment Release"]
D["A beta Efflux<br/>Impairment"]
E["Brain A beta<br/>Accumulation"]
F["BBB Transporter<br/>Dysfunction"]
G["Peripheral Blood<br/>sLRP1 Signal"]
A --> B
B --> C
C --> D
D --> E
C --> G
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style C fill:#e65100,stroke:#ffab91,color:#ffab91
style G fill:#e65100,stroke:#ffab91,color:#ffab91No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRP1 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 LRP1.
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 we stratify early-stage AD patients by degree of BBB dysfunction (using dynamic contrast-enhanced MRI permeability metrics) THEN plasma sLRP1 fragment concentrations will be significantly elevated | Plasma sLRP1 fragment levels (measured by ELISA targeting the extracellular domain) will be positively correlated with BBB permeability (Ktrans values) in AD pa | — no observation — | pending | 0.65 |
| IF we chronically inhibit ADAM10/17 activity (via pharmaceutical blockade or genetic knockdown) in 5xFAD transgenic mice starting at 3 months of age THEN brain microvascular endothelial sLRP1 protein | ADAM10/17 inhibition will reduce proteolytic shedding of LRP1 at the brain endothelium, preserving full-length LRP1 function and enhancing Aβ efflux capacity, a | — no observation — | pending | 0.58 |