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Title: The association of Alzheimer's disease and hypertension
Author: Burnett, Kimberley Anne
ISNI:       0000 0004 6056 8706
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Recent studies have suggested a link between Alzheimer's Disease (AD) and Hypertension (HTN) with midlife high blood pressure known to increase the risk of sporadic AD in later life, by approximately 1.5 fold. The molecular pathways and/or mechanisms that may link these two disease are yet to be fully understood, however evidence from a combination of observational human studies, animal models of HTN and the induction of HTN in animal models of AD implicated the renin angiotensin system, cerebral hypoperfusion, neuroinflammation, vascular dysfunction and oxidative stress in the association of AD and HTN. This body of work was designed to investigate·changes across the proteome in AD and HTN, using quantitative proteomics and human post mortem brain tissue from non-demented, normotensive control cases (C, NT), non-demented, hypertensive cases (C, HTN), normotensive AD cases (AD, NT) and hypertensive AD cases (AD, HTN). The results of this large scale experiment were analysed in silico at a functional level to highlight pathways and processes that show a high proportion of dysregulated proteins, and therefore may be pathologically involved in AD or HTN, in' isolation or together. A group of highly dysregulated proteins changing in both AD and HTN (dubbed convergence proteins) were identified for further investigation, using RT-PCR to investigate associated gene changes and immunohistochemistry to determine cellular distribution in the human brain. In the in silico analysis of quantitative proteomic data there were three strands of analysis performed; AD, NT vs C, NT (AD associated proteins); C, HTN vs C, NT (HTN associated proteins) and convergence proteins. In all analysis a high proportion of dysregulated proteins were involved in energy metabolism, reactive oxygen species and the cytoskeleton. While these changes can be linked to both vascular and AD pathology, they have been identified in the earliest stages of AD development and can also cause pathology leading to cognitive decline. In the further investigation of top changing convergence proteins a large amount of valuable and in some cases novel data was obtained. The identification of GSTI2, a potential antioxidant protein and CYTB, a component of complex III of the electron transport chain further support the identification of changes in proteins associated with energy metabolism in this investigation. Of particular interest, in terms of amount of quantitative data generated and also therapeutic potential, was the identification of decreases in CRABP1 in the frontal lobe and other areas in AD and HTN. This intracellular protein binds retinoic acid preventing it from acting at its nuclear receptors. A beneficial effect of retinoic receptor agonism on cognition and amyloid pathology has previously been identified in animal models of AD and a current clinical trial is underway to investigate the efficacy of a tricyclic antibiotic thought to have inhibitory effects on the catabolism of retinoic acid. While a certain amount of further work is required to fully investigate and validate the results of this investigation the data gather support current literature and provide novel data, in the study of some of the top changing convergence proteins in the human brain. The results of this investigation highlight the complex nature of both AD and HTN and potential pathways and mechanisms that may link the two but also provides potential avenues for further therapeutic intervention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available