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Title: Plasma proteins and related genes in Alzheimer's disease
Author: Cunningham Vardy, Emma Rachael Louise
ISNI:       0000 0001 3400 4876
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2007
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The pathogenesis of Alzheimer's disease (AD) is becoming an increasingly. complex field. The pathological hallmark of AD, the amyloid plaque, consists of, extracellular deposits of insoluble amyloid p-protein (AP). Ap is fonned from the . cleavage of the much larger amyloid precursor protein (APP). By measuring various plasma proteins implicated to have a role in AD pathology we sought to identify a specific and sensitive biomarker for AD. Relatively recently a number of peptidases have been discovered with the ability to degrade Ap peptide, including angiotensin converting enzyme (ACE) and neprilysin. Differences in levels of neprilysin and ACE have been found in postmortem human brain tissue between AD and controls.· A more intricate role for ACE in AD has been suggested by the prevalence of the ACE insertion polymorphism at intron 16 in AD as compared to controls, and the finding that the secretase releasing soluble ACE from its membrane-bound fonn might share identity with a-secretase, the enzyme responsible for the non-amyloidogenic processing of APP that precludes the pathological deposition of Ap in AD. The aim of this study was primarily to compare plasma levels of ACE and neprilysin in AD and control subjects and explore the nature of any changes over a two year period. Such data was to be supported by genotyping of individual samples for the ACE Insertion (1)/ Deletion (D) polymorphism. The study involved the recruitment of cases of AD from community-based memory clinics in both the Leeds and Dewsbury areas of West Yorkshire and age and gender matched· community-based controls. AD cases were seen at baseline and then every 6 months for 2 years (5 visits in total), whilst controls were seen only at baseline and at 2 years (2 visits in total). Although there was no difference in plasma neprilysin level detected between AD and control samples either at time of recruitment to the study or after two years, an alteration in plasma ACE was detected. Plasma ACE was found to be dependent on the ACE IID genotype, consistent with previous studies. A reduction ip. plasma ACE in AD was detected although as there was significant overlap in plasma ACE levels between AD cases and controls this plasma protein would not be suitable as a biomarker. Complementing these results cell culture work waS perfonned, showing a reduction of A~ in media samples from cells transfected with ACE as compared to control cells. Based on findings of differences in anthropometric measures between AD and' control subjects, and as there is a wealth of literature exploring the possible relationship between diabetes mellitus and AD, the study was extended to incorporate plasma insulin, insulin-like growth factor-l (lGF-I) and insulin-like growth factor binding protein 3 (lGFBP-3) measurements. IGF-l has also been shown to modulate growth and metabolic function in the brain and at the cellular level lower neuronal resistance to A~ toxicity, amongst other functions. Analysis of three polymorphisms in the Clock gene, a gene currently thought to be linked to insulin resistance and circadian rhythms, was also performed..This study showed no differences in terms of insulin between the AD and control groups, but did show raised free IGF-llevels in AD as compared to controls. The large degree of overlap in values of free IGF-I between AD and control subjects excludes this plasma protein as a candidate biomarker. Clock gene analysis revealed an association . . between one of the polymorphisms and crude measures of sleep disturbance.. Overall the study revealed varied and interesting findings, supporting' the requirement for further exploration of some of the factors studied in different subject groups, such as mild cognitive impairment, and over extended time periods.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available