Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased beta-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and beta-amyloid (A beta) are linked with vascular disease development and increased BACE1 and A beta accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Ap, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A beta 42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A beta 42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A beta 42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A beta 42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A beta 42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A beta 42. Lowering A beta 42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.