Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis.
Summary
This mechanistic study identifies APOA1 as a direct substrate of AEP, with AEP-mediated cleavage at N208 impairing cholesterol efflux and HDL formation. Genetic AEP deletion or pharmacologic blockade (inhibitor #11a) prevented APOA1 cleavage and markedly reduced atherosclerosis in ApoE−/− and LDLR−/− mice, positioning AEP as a translational therapeutic target.
Key Findings
- AEP is upregulated in human atherosclerotic plaques and cleaves APOA1 at residue N208.
- AEP activation impairs cholesterol efflux and HDL formation; AEP deletion attenuates atherosclerosis in ApoE−/− mice.
- Blocking APOA1 cleavage by N208A mutation or with AEP inhibitor #11a markedly reduces atherosclerosis in ApoE−/− and LDLR−/− mice.
Clinical Implications
While preclinical, the AEP–APOA1 axis offers a tractable pathway to enhance cholesterol efflux and HDL functionality; AEP inhibitors could complement LDL-lowering therapy in high-risk atherosclerosis if safety and efficacy translate to humans.
Why It Matters
It reveals a first-in-kind mechanism linking a lysosomal protease to HDL biogenesis failure and atherosclerosis and demonstrates targetability with a small-molecule inhibitor across two murine models.
Limitations
- Preclinical models may not fully recapitulate human lipoprotein metabolism and plaque biology
- Long-term safety and off-target effects of AEP inhibition were not evaluated in humans
Future Directions
Develop selective, clinically viable AEP inhibitors; validate APOA1 cleavage products as biomarkers; test target engagement and lipid/vascular effects in early-phase human trials.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- IV - Preclinical mechanistic evidence from animal models and human tissues
- Study Design
- OTHER