Introduction: β-amyloid (Aβ) is produced via the cleavage of amyloid precursor protein (APP) by β-secretase (BACE1), resulting in the formation of amyloid plaques, a hallmark Alzheimer’s disease (AD) pathology. AD, type 2 diabetes, obesity and cardiovascular disease appear intimately linked with endothelial dysfunction, inflammation, insulin resistance and elevated Aβ levels all common features. Impaired endothelial function is represented by impaired endothelium-dependent, nitric oxide (NO)-mediated relaxation. Tight regulation of vasoactive compounds such as endothelin-1 (ET-1) and NO are required to maintain vascular tone. An imbalance, resulting in increased ET-1 and reduced NO levels promotes vascular stiffening and consequently diseases such as diabetic retinopathy, nephropathy and stroke. Diseases caused by an increased atherosclerotic burden including coronary heart disease and stroke are major causes of death in obese and diabetic populations. Aims: Determine (1) whether enhanced Aβ levels are sufficient to induce vascular dysfunction and (2) if reducing Aβ production can reverse diet-induced vascular dysfunction. Methods: Measurements of vascular function was determined in vivo by the vascular response to Acetylcholine (endothelial dependent) or Sodium Nitroprusside (endothelial independent) using laser Doppler imaging in two studies; (i) Wild-type (C57bl/6) infused with murine Aβ42 or scrambled peptide (ScP) (3.36 μg/kg) in aCSF for 6 weeks mice fed a regular chow diet or (ii) a BACE1 inhibitor (M-3; 10 mg/kg) or vehicle (DMSO/PBS) into diet induced obese (DIO) C57bl/6 mice. Western blotting and ELISAs were used to measure vascular NO signalling and Aβ production. Results: Circulating levels of Aβ42, not the more prevalent Aβ40 isoform, are increased both in high fat feed mice and obese/diabetic human patients (P< 0.01). Infusion of M-3 into DIO mice rescued endothelial dependent reactivity (M-3 27.1 ± 5.9, vehicle 1.3 ± 2.9; P< 0.01). In contrast, infusion of Aβ42 promoted impaired vascular responses (Aβ42 14.1 ± 3.7, ScP 38.3 ± 3.2; P< 0.001) on regular chow with no change in body weight. In line with our hypothesis, infusion of Aβ42 increases the ET-1/NO ratio (ScP 1.12 ± 0.05, Aβ1-42 5.35 ± 0.89; P< 0.001), while DIO mice treated with a BACE1 inhibitor, thus with reduced plasma Aβ42levels, have a low ET-1/NO ratio (M-3 1.29± 0.9, DIO 4.62 ± 1.3; P< 0.05). Conclusions: We suggest that amyloid processing has a role in normal vascular function with aberrant processing leading to endothelial dysfunction and hypertension. Here we show that pharmacological inhibition of BACE1 can reverse diet induced endothelial dysfunction, via modulation of Aβ42 levels, as infusion of Aβ42 can promote the dysfunction independent of a high fat diet. Implications: Our data suggest that plasma Aβ42 could be a novel bio-marker for diabetes-induced vascular disease and thus BACE1 inhibitors, currently in clinical trials for AD, may be an innovative treatment.