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Title: An investigation of beta-secretase activity and regulation in Alzheimer's disease
Author: Liu, Wei Wei
ISNI:       0000 0001 2430 9713
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2007
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Alzheimer's disease (AD) is the most common cause of dementia, characterized by the • presence of extracellular amyloid plaques and intracellular tangles in the brain. The principal component of amyloid plaques is the amyloid 13 (A13) peptide, cleaved from amyloid precursor protein (APP) by 13-secretase and y-secretase. Two proteases with 13-secretase activity have been identified: 13-site APP-cleaving enzymes 1 and 2 (BACE1 and BACE2). Previous post. mortem studies have revealed an increase of 13-secretase activity in brain tissue of individuals with sporadic AD. This study aimed to investigate whether platelet 13-secretase activity was elevated in individuals with AD or mild cognitive impairment (MCI). An assay of 13-secretase activity was established and characterised (chapter 3) using small peptide f1uorogenic sUbstrates, based on the region of APP which 13-secretase normally cleaves. This assay was then applied to a large group of platelet samples from individuals with AD. or MCI, or from controls (total 331 samples) (chapter 4). This· work revealed that although there was considerable variation in platelet 13-secretase activity between individuals. the group of people with AD or MCI had a statistically significant higher activity than did age-matched controls. We then investigated a range of factors that could potentially contribute to the inter-individual variation in 13-secretase activity. Platelet 13-secretase activity did not correlate with BACE1 protein level in a subset of samples (n = 28). indicating that it might be regulated by factors other than BACE1 expression. Interestingly, a significant correlation between platelet membrane 13-secretase activity and platelet membrane cholesterol level was identified. This led tQ our investigation of the relationship between membrane. cholesterol level and membrane 13-secretase activity in SH-SY5Y cells (chapter 5). This work revealed a reciprocal and biphasic relationship between membrane cholesterol level and membrane 13-secretase activity. a relationship that may also be present in human platelets
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available