Comparison of the activity and expression of the BACE family of proteins with genetic/splice variants, and the associations with disease.
A hallmark of Alzheimer's Disease are plaques in the brain, which are made up of small fragments of protein called amyloid beta peptides. Amyloid beta peptides are produced via cutting of the amyloid precursor protein (APP) by beta secretase 1 (BACE1). BACE1 activity is increased in Alzheimer's Disease, and is therefore pivotal to the development of the disease. Research on the role of BACE1 outside of Alzheimer's Disease is limited. Recently, increased BACE1 activity has been implicated in other functions and diseases, including diabetes and obesity. BACE1 has been a therapeutic target of interest over the past couple of decades. However, to date there has not yet been any success, with clinical trials ending due to no improvement or worsening of cognitive function, or due to safety concerns. Several BACE1 inhibitors have been reported to also target BACE2, some to a greater extent than BACE1. BACE2 is a family member of BACE1, known to compete for the same substrates. The wide-ranging reported side effects of these drugs highlight the limits in understanding of the roles of BACE1 and BACE2.
We believe that BACE1 and BACE2 have a range of functions that are not yet understood, and may be implicated in other diseases. Recently BACE1 has been linked to obesity, diabetes mellitus, cancer and cardiovascular disease. We will use a wide range of UK Biobank data to look at whether changes in BACE1 and BACE2 activity are related to genetic variations between people. The amount of data available on UK Biobank will then allow us the excellent opportunity to study BACE1 and BACE2 relevance to many diseases. This may shed light on new roles of these enzymes in disease, and due to the existence of BACE1 inhibitors, provide novel uses for these drugs.
This project will be undertaken over approximately 3 years, contributing towards a PhD project. We hope the findings will shed light on the role of BACE1 and BACE2 in disease, and potential mechanisms behind the increases in BACE1 activity observed in various diseases. Ultimately, we hope that it may lead to novel targets for BACE1 inhibitors, which could have a significant impact on the treatment of disease, and a potential for a personalised medicine approach.