Investigating the physiological function of BACE1 and its role in metabolism

Abstract

Dementias are now considered to be the 5th greatest cause of death worldwide and the leading cause of death in the UK. One of the biggest problems facing Alzheimer’s Disease (AD) research is the time difference between disease onset and diagnosis in sporadic cases; with many patients only exhibiting symptoms after decades of living with AD pathologies. Due to this, current understanding of the early stages of this dementia is extremely limited but the pathogenic production of amyloid is currently considered the earliest change in AD development.

The presence of neurotoxic amyloid is a hallmark of AD. This peptide aggregates to form the characteristic plaques that are used to diagnose AD post-mortem. The rate limiting step in amyloidogenesis is the activity of the aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Whilst the function of this enzyme has been well studied within the context of AD, very little is known about its physiological function within healthy organisms. However, studies have identified that BACE1 KO mice are resistant to diet-induced obesity and its comorbidities and BACE1 protein expression is known to increase in obesity- a known risk factor for AD.

This thesis aims to test the hypothesis that metabolic dysfunction as a result of chronic high-fat feeding leads to changes in BACE1 activity, thereby increasing the susceptibility of developing AD. To do this, proteomic analysis of hippocampal and hypothalamic tissues from chow fed and high-fat fed mice were compared alongside a BACE1 proximity assay to determine novel BACE1 interacting proteins. A further study was designed to test the hypothesis that amyloid peptides lead to leptin resistance- a possible contributor to central memory and metabolic impairment. These studies suggest a role for BACE1 in the regulation of cell connectivity and communication, which may underlie the changes in central metabolic and memory circuitry seen in both obesity and AD.

Date of Award	2020
Original language	English
Awarding Institution	University of Dundee
Sponsors	Alzheimer's Society & Alzheimer's Research UK
Supervisor	Rory McCrimmon (Supervisor) & Michael Ashford (Supervisor)