AbstractAlzheimer’s disease (AD) is the most common cause of dementia, accounting for around 60-70% of cases. AD encompasses large-scale neuronal loss, resulting in progressive memory and other cognitive decline. Presently, there is no cure for dementia and in light of the ageing population demographic, this represents a clear unmet medical and socioeconomic challenge Worldwide. Much of the current AD research focuses on studying the brain once hallmark amyloid plaque and neurofibrillary tangle pathologies have presented. However their appearance is extremely end stage and to date, any therapeutic interventions aimed at alleviating them having failed to halt symptoms progression. It may therefore be beneficial to look for earlier changes, with metabolic and oxidative stress events as well as reduced cerebral metabolism thought to occur early on in disease progression.
Evidence from rare, familial AD cases suggests a causative role for A in AD pathogenesis. For this reason, the enzyme beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), the rate-limiting step in A production is currently of great therapeutic interest. With the prevailing view being that reducing BACE1 levels will be beneficial in AD, there remains a need to better understand the physiological roles of BACE1 to avoid potential side effects of BACE1 inhibition.
Herein is presented data showing that, in agreement with the previous literature, BACE1 is fundamentally regulated by cell stress. Notably, both acute and prolonged bouts of oxidative and metabolic stress result in significant increases in BACE1 and APP protein expression. These changes also result in a shift in APP metabolism, with amyloidogenic processing of APP predominating during times of stress.
It has also been shown that chronic elevation of BACE1 and/or manipulation of APP processing can alter cellular glucose uptake and use. These changes were determined through the use of radiolabelled substrate uptake and oxidation as well as extracellular flux assays. These data highlighted a fundamental shift in cellular metabolism, with aerobic glycolysis being utilised over oxidative metabolism of glucose. These changes were later shown to come as a result of metabolic lesions, which acted to impair substrate delivery to the electron transport chain of the mitochondria. Taken together, these data show that overexpression of the AD-associated protein BACE1 phenocopies a number of the earliest detectable changes observed in the brains of people who later develop AD.
Finally, these data highlighted the potential importance of a number of novel pathways (Sirtuin, AMP-activated protein kinase, and peroxisome proliferator-activated receptor- coactivator signalling) that may underlie these changes and offer therapeutic avenues for earlier and more targeted treatment to halt AD progression.
|Date of Award||2014|
|Sponsors||Alzheimer's Research UK|
|Supervisor||Michael Ashford (Supervisor) & Calum Sutherland (Supervisor)|
- Alzheimer's disease
- Glucose metabolism