Towards an Understanding of BACE1 Activity in the Occurrence of Vascular Dementia

Background: Vascular dementia is the second most prolific form of dementia after Alzheimer’s disease and is hallmarked by cognitive decline. Currently, there is no direct treatment for vascular dementia. Previous works have pointed towards links between vascular dementia, insulin resistance and endothelial dysfunction. BACE1 has recently been shown to cleave the insulin receptor, potentially driving insulin resistance. Subsequently, insulin resistance is characterised by an imbalance between vasoactive compounds ET-1 and nitric oxide synthase, leading to endothelial dysfunction. Objective: Here we examine the impact of the modulation of BACE1 activity on the insulin stimulated Akt and eNOS signalling pathway in the endothelium, in order to assess the contribution of BACE1 to endothelial dysfunction. Methods: Murine peripheral and brain endothelial cells were isolated from wild type and BACE1 knockout mice, with a portion of wildtype cells being treated with a BACE1 inhibitor. Cells were stimulated with insulin before cellular protein content was harvested and analysed by western blot for changes in Akt and eNOS activity. Results: Phosphorylation of eNOS and Akt was increased when BACE1 was inhibited genetically or pharmacologically in peripheral murine endothelial cells. Genetic knockout of BACE1 contributed significantly to increases eNOS phosphorylation (P = 0.0276). With pharmacological inhibition of BACE1 also making significant contributions to eNOS phosphorylation (P = 0.0001). However, the same signalling differences in murine brain endothelial cells were not clearly observed. This is likely due to the lack of data available for this cell line. Conclusion: Such demonstrable improvements suggest BACE1 may be a suitable target for the treatment and management of peripheral diseases with underlying endothelial dysfunction. Should results in BECs follow the same pattern of improved Akt and eNOS phosphorylation then BACE1 may considered as a plausible drug target for the treatment of cerebrovascular impairments