Soluble Aβ oligomers trigger endothelin-1 and ROS-dependent pericyte contractile stress, and repeated exposure converts this acute vasoactive injury into a secondary senescence phenotype. In this model, pericyte senescence is downstream of amyloid toxicity but may later amplify BBB dysfunction and hypoperfusion.
Curated pathway from expert analysis
flowchart TD
A["APP Full Length<br/>Membrane Protein"]
B["BACE1 Beta-Secretase<br/>Cleavage at beta-site"]
C["sAPPbeta + CTFbeta<br/>C-terminal Fragment"]
D["Gamma-Secretase Complex<br/>PSEN1/PSEN2"]
E["Abeta42 Peptide<br/>Amyloidogenic Fragment"]
F["Abeta Oligomers<br/>Toxic Aggregates"]
G["Amyloid Plaques<br/>Extracellular Deposits"]
H["ADAM10 Alpha-Secretase<br/>Non-amyloidogenic Path"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
A --> H
H -.->|"competes with BACE1"| B
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for APP/Aβ, EDN1, EDNRA, ROS 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 APP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived brain pericytes are exposed to 200 nM soluble Aβ42 oligomers pulsed every 48 hours for 14 days (7 exposures total), THEN SA-β-gal positive cells will increase to ≥30% and p16Ink4 | SA-β-gal positivity will reach ≥30% (vs. <5% in controls) and p16Ink4a expression will increase ≥3-fold in repeatedly Aβ42-exposed pericytes | — no observation — | pending | 0.60 |
| IF human iPSC-derived brain pericytes are treated with 500 nM soluble Aβ42 oligomers for 4 hours, THEN phospho-MLC2 (Ser19) levels will increase by ≥50% compared to vehicle-treated pericytes, indicati | Phospho-MLC2 (Ser19) will increase ≥50% in Aβ42-treated pericytes vs. vehicle control (expected ~2.5× baseline fold change) | — no observation — | pending | 0.70 |