BACE1 activity as a determining factor in atherosclerosis development?

Background: The protease β-site APP-cleaving enzyme 1 (BACE1) is directly associated with Alzheimer's disease (AD) development, the production of β-amyloid peptides and amyloid plaques, both hallmarks of AD pathology. AD, atherosclerosis and cardiovascular disease appear intimately linked, with endothelial dysfunction, inflammation and insulin resistance common features. Tissue BACE1 activity is increased by chronic stress (e.g. oxidative, metabolic or inflammatory) while inhibition improves obesity and diabetes via a rapid anti-inflammatory response. Therefore we examined the vascular expression profile of BACE1 and how BACE1 inhibition affects endothelial function and atherosclerosis in ApoE knockout (KO) mice.

Methods: Human temporal arteries from clinically diagnosed control and atherosclerotic patients were obtained from Tayside Tissue Bank and immuno-histological staining performed for BACE1 detection. ApoE KO mice (8 weeks old) were fed a Western diet (45% fat + 0.15% cholesterol) to induce atherosclerosis. Vehicle or BACE1 inhibitor (Merck-3) were administered via a subcutaneously implanted osmotic minipump for 28 days. Endothelial function, using laser Doppler imaging, blood pressure and glucose homeostasis were measured.

Results: In non-diseased human temporal artery BACE1 is expressed in endothelial and smooth muscle cells. This staining is increased in atherosclerotic temporal artery and is evident in atherosclerotic plaques. Merck-3 treatment of ApoE KO mice enhances in-vivo vascular responses to Acetylcholine (P<0.001), reduces hypertension (P<0.05) and improves insulin resistance (P<0.05) compared to controls.

Conclusions: We suggest that BACE1 has a role in normal vascular function, in the development of atherosclerosis and that BACE1 inhibitors may be a novel therapy for atherosclerosis and vascular disease.