NSAIDs, fatty acids and cholesterol as modifiers of pathology in rodent models of Alzheimer's disease

Abstract

Alzheimer's disease, the most common type of senile dementia, is characterised by p-amyloid plaques, neurofibrillary tangles and neuronal loss. Amyloid plaques are associated with the increased inflammation and oxidative stress. Rodent models overexpressing APP are a useful tool to investigate both the processes and the consequences of amyloid generation, and are crucial for developing and testing hypotheses about treatments and risk factors. Tg2576 transgenic mice overexpress human 'Swedish' mutated APP and show memory impairment followed by amyloid plaques pathology. GP56 rats also overexpress human 'Swedish' mutated APP, but show no signs of AD-like pathology. In this thesis, I explored the influence of dietary and pharmacological modifications on pathogenesis of AD as tested in rodent models. As epidemiological data implicated the role of non-steroidal anti-inflammatory drugs (NSAIDs) in reducing the risk of AD, I investigated the role of ibuprofen as either prevention or treatment in transgenic mice. The results indicated that ibuprofen delayed the onset of behavioural impairment but only when it was administered early during the evolution of their pathology. Levels of Ap and plaque pathology were not affected. Also consumption of n-3 fatty acids seemed to reduce the risk of AD, possibly by acting as an anti-oxidant. Thus I investigated the effect of DHA on learning ability and pathology in AD mice. Administration of DHA to young mice reduced the impairment in learning but did not alter Ap levels or plaque pathology. Finally the role of high cholesterol diet was investigated in GP56 rats. Feeding rats for 8 weeks did not induce any amyloid-connected pathology. The results indicate that modulation of inflammatory processes, or lipids can have modest ameliorating effects on behavioural impairments in rodent AD models, provided intervention is undertaken early, but suggest these may not be the most efficacious targets for therapeutic intervention