Analysis of anatomical neuronal changes in the brain of a mouse model of alzheimer's disease

Neuronal loss and cell death are characteristics of Alzheimer's disease (AD). Recent evidence shows that type 2 diabetes (T2DM) is a risk factor for AD and that impairments in insulin signalling can contribute to neurodegeneration and cognitive decline. As a result of this impairment, insulin is likely to be ineffective in the treatment of AD. A novel strategy to treat AD is to normalise insulin signalling in the brain, e.g. by the use of novel enzyme-resistant glucagon-like peptide-l (GLP-l) and glucose- dependent insulinotrophic polypeptide (GIP) analogues that have been developed to treat T2DM. In the brain, GLP-l acts as a growth factor and possesses neuroprotective properties. The aims of this thesis were to investigate the location of GLP-l and GIP receptors in the brain in relation to the IR in order to provide insight into possible roles of GLP-l and GIP in the brain. As GLP-l and GIP have been proposed to promote neurogenesis, studies were done to investigate neurogenesis in the brain of mouse models of AD and to establish the effect of treatment with incretin analogues on neurogenesis. To summarise the findings of this thesis, GLP-l, GIP and insulin receptors were found to have a similar expression pattern, with receptors primarily located on neurons. Furthermore these receptors were all present in the cortex and hippocampus, which are areas involved in learning and memory. With respect to neurogenesis, both diabetes and AD were found to impair neurogenesis in the hippocampus presenting further support to evidence showing a link between AD and T2DM. Treatment with GLP-l or GIP mimetics rescued this deficit. These findings suggest that damage occurs in the AD and in the diabetic brain and that treatment with GLP-l or GIP mimetics has the potential to act in a regenerative manner and therefore have the potential to be developed as novel therapeutics for the treatment of AD.EThOS - Electronic Theses Online ServiceGBUnited Kingdo