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Title: Analysis of the effects of novel long-acting GIP agonists on neurodegenerative hallmarks in a mouse model of Alzheimer's disease
Author: Duffy, Aisling
ISNI:       0000 0004 5990 3562
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2016
Availability of Full Text:
Full text unavailable from EThOS. Thesis embargoed until 01 Apr 2018
Alzheimer's disease (AD), a devastating neurodegenerative disorder which causes progressive decline in cognitive function, is increasing dramatically in prevalence due to our ageing population. Presently, there are no disease modifying treatments available for AD, therefore development of novel drugs is desperately needed. AD has strong association with diabetes due to significant disturbances to insulin signaling in the AD brain. This thesis furthers the investigation into the potential of incretin peptides, currently approved as treatment for type 2 diabetes, in the treatment of AD. Studies presented here have demonstrated that the Glucose-dependent insulinotrophic peptide (GIP) analogue, DAla2GIP, significantly reduces beta-amyloid plaque load, inflammation and oxidative stress in the APP jPS1 mouse model of AD. A longer acting derivative of GIP analogue, DAla2GIP(Lys37PAL) was characterized in wild-type mice where a dose response study demonstrated safety and tolerability, with 25nmoljkg showing significant efficacy in potentiating neurogenesis. The effect of chronic administration of DAla2GIP(Lys37PAL) in the APP jPS1 mouse model is reported for the first time, compared head-to-head with liraglutide, a Glucagon-like peptide-1 (GLP-1) analogue with proven efficacy in the amelioration of cognitive impairment and histological hallmarks of AD. While liraglutide alone significantly improved recognition memory in APP/PS1 mice, DAla2GIP(Lys37PAL) alone failed to ameliorate cognitive deficits in the APP jPS1 mice. DAla2GIP(Lys37PAL) plus liraglutide in combination demonstrated no additive effects compared with liraglutide treatment alone. Dual knockout of GIP and GLP-1 receptors did not cause significant impairments in learning and memory. DIRKO mice showed improvements in spatial memory and enhanced L TP, suggesting more effective compensatory mechanisms than single incretin receptor knockout mice. This thesis demonstrates that both GIP and GLP-1 analogues show therapeutic potential for the treatment of Alzheimer's disease. Despite activating similar downstream mechanisms, administration of GIP and GLP-1 analogues is associated with different behavioural effects, which should be further investigated as the research area progresses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available