The current global epidemic of obesity and diabetes is driving an increased incidence of cardiometabolic disease. Microvascular abnormalities have been found to be an important underling pathology of a number of cardiometabolic diseases. Indeed, microvascular dysfunction, the inability of the microcirculation to feed tissues adequately, is strongly associated with type 2 diabetes and obesity, atherosclerosis, stroke and dementia. Thus, targeting the mechanisms by which nutrient excess drives the induction of microvasculardysfunction could reduce cardiovascular disease prevalence.    Our work has revealed that a protein called BACE1, more commonly associated with Alzheimer’s disease, plays an important role in type 2 diabetes and obesity. BACE1 activity is required for the production of β-amyloid peptides, from the amyloid precursor protein, which form the characteristic amyloid plaques found in Alzheimer’s disease. There is growing evidence that Alzheimer’s disease, diabetes and cardiovascular disease are intimately linked, with inflammation, oxidative stress and insulin resistance common features. BACE1 protein is expressed in a wide variety of tissues and cells, including vascular smooth muscle and endothelial cells. Expression level and activity are increased by chronic stress (e.g. oxidative, metabolic and inflammatory) and we have shown that high fat diet drives its transcription and translation.    We have shown that global deletion of BACE1 in mice enhances insulin sensitivity and protects against diabetes-induced endothelial dysfunction. Importantly, pharmacological inhibition of BACE1 can restore metabolic and vascular health in mouse models of disease. These effects are via modulation of BACE1 cleavage of both the amyloid precursor protein and the insulin receptor, which we recently identified as a novel substrate of BACE1. Furthermore, we have also demonstrated that this role translates into human physiology, with BACE1 activity inversely correlated with endothelial and vascular dysfunction.   Therefore, our research focus in on determining whether BACE1 can be a novel drug target to provide an innovative therapy for type 2 diabetes and its vascular co-morbidities. With BACE1 inhibitors currently in clinical trials for AD, repurposing these drugs for cardiometabolic disease this could be a promising strategy.