increased expression of APP and BACE1 and the production of Aβ peptides, whereas exogenous NO reduces APP, BACE1, and Aβ levels in cerebral microvessels (23). Thus, there appears to be an interesting reciprocal connection between BACE1, APP processing, Aβ levels, and NO bioavailability. Hyperglycemia and hyperlipidemia increase BACE1 activity and Aβ peptide levels in tissues and plasma (24, 25), linking key metabolic disease markers with increased amyloid processing. Consequently, we hypothesized that the development of type 2 diabetes (T2D) and/or obesity elevates circulating Aβ levels, which in turn drives vascular dysfunction. We tested this hypothesis in 3 ways: firstly, by reducing BACE1 activity genetically and pharmacologically in mice and ascertaining how this modified diet-induced endothelial dysfunction; secondly, by increasing plasma Aβ levels, indirectly through overexpression of mutant human APP genes and directly by Aβ peptide infusion, to promote vascular dysfunction in mice; and thirdly, by cross-sectionally examining the association between plasma Aβ levels and endothelial function in patients with T2D.