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Title: Modulation of inflammation and insulin resistance associated with Alzheimer's disease and dietary-induced cognitive dysfunction
Author: Denver, Paul
ISNI:       0000 0004 7226 2093
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2017
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Alzheimer's disease is a neurodegenerative condition, characterised by cognitive decline and aggregations of misfolded proteins in the brain. With improving healthcare and extension of life expectancy, prevalence of Alzheimer’s disease continues to rise as a consequence of advanced age. Some drugs are available that offer symptomatic relief in Alzheimer's disease, however, none exist that alter the disease course. Diabetes and obesity increase the risk of developing Alzheimer’s disease; inflammation and insulin resistance are thought to mediate this association. Data presented in the following chapters demonstrate a time course of disturbed cognition, inflammation and insulin signalling in the brain that progresses in the early stages of the development of high-fat diet-induced obesity. Notable decline in working and spatial memory was induced in chronically high-fat diet-fed mice and these deficits were not corrected in mice treated with Xenin- 25 [Lys (13) PAL], a long-acting analogue of gut hormone xenin-25. Genetic and protein markers of inflammation and insulin signalling were also dysregulated in the brains of 21-week high-fat diet-fed mice, many of which were corrected following Xenin-25 [Lys(13)PAL] treatment, representing previously unreported findings. Using an aged APP/PS1 mouse model of Alzheimer’s disease, striking similarities with age-matched wild-types were apparent. However, spatial learning was impaired and increased insulin resistance was apparent in the brains of APP/PS1 mice. Three gut hormone analogues, liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25rLys(13]PAL] were shown to have positive effects on cognitive function and reduced amyloid-(3 burden in the brains of APP/PS1 mice. Finally, a novel immunomodulatory polysaccharide that enhances the adaptive immune system showed promising effects in the APP/PS1 model, underscoring the therapeutic potential of this compound, suggesting that augmentation of certain immune responses may be a viable treatment approach for Alzheimer's disease. This thesis demonstrates similarities between the pathogenesis of diabetes, obesity and Alzheimer's disease. Results here show that brain insulin resistance in APP/PS1 mice occurs in the absence of peripheral metabolic dysregulation, suggesting that brain insulin resistance in Alzheimer's disease is a distinct pathological phenomenon, divergent from typical metabolic disease. Modulation of inflammatory and insulin signalling pathways, using pharmacological peptides and natural compounds has potential to alter the disease course of Alzheimer's disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available