Determining how BACE1 activity regulates neuronal glucose metabolism

A high proportion of the UK population is obese and this is associated with significantly increased risk of type 2 diabetes (T2D), cardiovascular disease and Alzheimer’s disease (AD).  AD is also associated with increased risk of T2D and AD patients and AD animal models demonstrate disturbances in glucose metabolism. The aspartic protease BACE1 (beta-site amyloid precursor protein (APP)-cleaving enzyme) is thought to be the primary driver for the neurodegeneration and cognitive dysfunction associated with AD. The amount of BACE1 in tissues increases with age and is markedly raised by pathological stresses (e.g. oxidative, metabolic or inflammatory).  We have demonstrated that inhibition of BACE1 (genetically or pharmacologically) prevents or reverses diet-induced obesity and improves whole-body insulin sensitivity and glucose disposal. One hypothesis is that inhibition of BACE1 rapidly reverses the hyperleptinaemia associated with obese state (our data support this) to re-sensitise the animal to endogenous (lower) leptin.  As leptin is mainly made and secreted by white adipose tissue (WAT), this may be the site for BACE1 action relative to the obese state.

The project will: (i) determine leptin expression, content and release from human and murine adipocytes /cell lines in relation to BACE1 levels and activity and (ii) analyse the molecular mechanisms by which BACE1 regulates leptin in WAT.

Supervisor: 
Professor Mike Ashford
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