LRP1 mediates Aβ export from brain to blood at the BBB. Metalloprotease-mediated shedding of the LRP1 ectodomain (sLRP1) generates circulating fragments that retain Aβ-binding capacity but lack transmembrane signaling. Elevated sLRP1 indicates LRP1 dysfunction and impaired Aβ clearance, occurring before amyloid plaque formation. This hypothesis links Aβ clearance mechanisms directly to BBB dysfunction.
Curated pathway from expert analysis
flowchart TD A["Metalloprotease Activation"] --> B["LRP1 Ectodomain Shedding"] B --> C["sLRP1 Elevation in Blood"] C --> D["LRP1 Dysfunction at BBB"] D --> E["Impaired Abeta Transcytosis"] E --> F["Reduced Abeta Clearance from Brain"] F --> G["Abeta Accumulation in Brain"] D --> H["BBB Endothelial Dysfunction"] G --> I["Amyloid Plaque Formation"] H --> I G --> J["Neuronal Toxicity"] J --> K["Cognitive Decline"] I --> K F --> J G["Abeta Accumulation in Brain"] --> L["Memory Impairment"] K["Cognitive Decline"] --> M["AD Progression"]
No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRP1 (LDL Receptor Related Protein 1) 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 (LDL Receptor Related Protein 1).
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 soluble LRP1 (sLRP1) ectodomain shedding indicates impaired LRP1-mediated Aβ clearance at the BBB, then elevated plasma sLRP1 will predict reduced CSF/plasma Aβ42 ratio and slower Aβ clearance rate | In AD/MCI patients (n≥80), high plasma sLRP1 (top quartile) correlates with reduced CSF/plasma Aβ42 ratio (r<-0.45), decreased peripheral Aβ clearance rate (40- | — no observation — | pending | 0.73 |