Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which there is no cure. At the neuropathological level, AD is characterized by the presence of large numbers of amyloid-beta containing plaques (Aβ-plaques), and neurofibrillary tangles comprised mostly of hyperphosphorylated aggregated protein tau. Both types of deposit are associated with neuroinflammation, synaptic and neuronal cell loss. Accumulating evidence indicates a role for metabolic dysfunction in the pathogenesis of AD. Type 2 diabetes increases the risk of developing AD and several post-mortem analyses have reported evidence of insulin resistance in Alzheimer brain tissue. Insulin-based therapies have emerged as potential strategies to slow cognitive decline in AD, these include the use of insulin sensitizers, such as rosiglitazone, which mediates its effects on insulin sensitivity via the peroxisome proliferator-activated receptors-gamma (PPAR-γ) receptor. While the results of insulin sensitizers on cognition in animal models of AD have been largely positive, the impact of these compounds on cognitive decline in AD patients has been variable. Animal experiments provide a unique opportunity to examine the specific conditions and mechanisms by which insulin sensitizer’s impact on AD-related pathology. This thesis details experiments conducted in a popular Amyloid Precursor Protein overexpressing transgenic mouse model of amyloid pathology that overproduces human Aβ. The aim of these experiments was to determine if chronic dosing with rosiglitazone ameliorated phenotypic behavioural deficits in transgenic mice, and lowered specific biomarkers associated with Aβ over-production. The results indicate that rosiglitazone largely does not reverse phenotypic behavioural alterations in these mice, nor does it reduce total Aβ levels. From this preclinical data, it is concluded that rosiglitazone is likely not a suitable therapeutic treatment for use in human patients with AD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:585291 |
| Date | January 2013 |
| Creators | Anderson, John Daniel |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/52635/ |
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