Investigating the role of BACE1 in angiogenesis

β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease notorious for its contribution to the aetiology of Alzheimer’s disease (AD). Notably, BACE1 is elevated in diseases displaying aberrant angiogenesis, including diabetes mellitus (DM), and is implicated in VEGF Receptor 1 (VEGFR1) proteolysis (Devi et al., 2012 and Cai et al., 2012). Therefore, we hypothesise that increased BACE1 activity in DM contributes to the altered angiogenesis displayed in associated microvascular complications, including diabetic foot ulcers (DFUs), and that BACE1 inhibitors may prevent such problems. In vivo observations of the endothelium in the retina of BACE1-/- mice displayed a hyper-branching phenotype in comparison to wild types. This was characterised by a decrease in radial outgrowth but an increase in branch points, percentage vasculature area and quantity of filopodia. This finding was further supported in vitro when exploiting the fibrin gel angiogenesis assay. Here, BACE1 inhibition of human umbilical vein endothelial cells (HUVECs) exhibited an increase in sprouting (17 ± 3%, P=<0.001) compared to controls. Lastly, an increase in the phosphorylation of eNOS at Serine 1177 in HUVECs (+ 0.8 ± 0.2, P=0.05) and primary lung endothelial cells (PECs) (+ 0.2 ± 0.02), prior to VEGF stimulations, provided a possible insight into the pro-angiogenic mechanisms of BACE1 inhibition. Overall, our findings suggest that BACE1 inhibitors, previously trialled to treat AD, could be repurposed to normalise angiogenesis in DM. This may reduce the risk of microvascular complications from developing and prevent consequent amputations.