Soluble PDGFRβ (sPDGFRβ) is released into the bloodstream upon pericyte damage, serving as a peripheral indicator of blood-brain barrier (BBB) pericyte coverage loss. Elevated plasma sPDGFRβ correlates with BBB leakage and cognitive decline trajectories. The mechanism involves ADAM10/ADAM17-mediated ectodomain shedding of PDGFRβ from damaged pericytes. This hypothesis has the strongest evidence base with human validation in Alzheimer's disease (AD) and vascular dementia cohorts. Specificity concerns regarding peripheral PDGFRβ+ cell sources (vascular smooth muscle cells, hepatic stellate cells) are addressable through cell-type-specific validation studies and parallel peripheral biomarker controls.
Curated pathway from expert analysis
flowchart TD
A["PDGFRbeta<br/>Pericyte Receptor"]
B["PDGF-BB<br/>Ligand Signaling"]
C["Pericyte<br/>Detachment"]
D["BBB<br/>Compromise"]
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:#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 PDGFRΒ yet. Search RCSB →
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 PDGFRβ.
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 pericytes are selectively ablated via genetic or pharmacological targeting in a mouse model of neurodegeneration (APP/PS1 or 5xFAD cross with PDGFRβ-Cre:DTR system), THEN plasma sPDGFRβ levels will | Plasma sPDGFRβ elevation to >150% of baseline by day 14, followed by >20% increase in escape latency by day 21 in pericyte-ablated vs. control mice. | — no observation — | pending | 0.78 |
| IF human cohorts with mild cognitive impairment or early Alzheimer's disease are stratified by presence/absence of peripheral PDGFRβ+ cell pathology (hepatic fibrosis stage ≥F2, or carotid intima-medi | Hazard ratio >1.8 for progression to dementia over 24 months in the high sPDGFRβ tertile vs. low tertile, independent of peripheral organ involvement. | — no observation — | pending | 0.82 |