The role of BACE1 in vascular dysfunction associated with metabolic disease and dementia

Beta secretase 1 (BACE1) is a well-established causative molecule in Alzheimer’s Disease where it’s cleavage of the amyloid precursor protein produces amyloid beta peptides (Aβ). BACE1 has an emerging role in vascular dysfunction which is less well defined. Numerous BACE1 inhibitors have made it through varying stages of clinical trials, offering the potential for drug-repurposing in the context of both Alzheimer’s Disease, and vascular disease and dementia. The general aim of this project is to define the role of BACE1 in the vascular dysfunction frequently observed in metabolic dysfunction and dementia.

To identify novel BACE1 substrates and pathways, and physiological roles, which may be important underlying mechanisms in cardiometabolic and cerebrovascular diseases, and dementia, a data mining and bioinformatics approach was used. This identified 533 BACE1 regulated proteins, including 120 putative substrates. Experimental validation in BACE1 knockout brain endothelial cells identified PTPRD and DCC as putative novel BACE1 substrates.

To investigate downstream functional pathways and genes altered by upregulated expression of BACE1 in disease, bioinformatic analysis was done on RNA-sequencing of hCMEC/d3 brain endothelial cells overexpressing BACE1. This identified associations with ‘insulin resistance’, and ‘lipids and atherosclerosis’ (p<0.05). It also identified MAF BZIP Transcription Factor F (MAFF) as a potentially novel regulator of BACE1, and associations with the inhibitor of DNA binding (ID) family.

To investigate the effect of changes in BACE1 expression on the plasma proteome, and potential biomarkers, UK Biobank data was analysed. This identified a signature of 28 plasma proteins associated with BACE1 eQTLs. Five uncharacterised BACE1 eQTLs were associated with significant differences in plasma Aβ40/42 (p<0.05), one of which was associated with significantly increased plasma Aβ40.

Together, this analysis has identified novel substrates, regulated proteins, eQTLs and potential plasma protein biomarkers related to BACE1 which may have important implications in shared mechanisms underlying vascular dysfunction.