Year: 2012
Type: dissertation
Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases. However, \nthe aetiology of AD is still unclear and there is currently no cure. In order to develop new \ntherapeutic strategies more basic research into the underlying mechanisms leading to \ncognitive impairment is needed. This thesis uses the Tg2576 mouse model to examine the \neffects of amyloid pathology on hippocampal network activity and memory, and to assess the \ntherapeutic effects of exercise as a lifestyle intervention against amyloid-induced cognitive \ndecline. \nThe hippocampal network is made up of different structural sub-regions, dentate gyrus (DG), \nCA1 and CA3, each of which plays a different role in memory encoding and retrieval. An \nanalysis of c-fos expression was carried out followed by structural equation modelling to \nassess neural activity in each sub-region when Tg2576 and wild-type control mice explored a \nnovel or familiar spatial environment. In young transgenic mice there was a reduction in DG \nengagement when encoding spatial novelty compared to controls. In aged mice deficits in \nDG engagement were seen in both genotypes. The influence of amyloid-induced \nhippocampal network alterations on cognition was assessed on a novel task designed to test \nconfigural integration of cues relating to episodic memory. An analysis of c-fos expression \nin normal mice revealed that this task was also DG dependent. Marked deficits in episodiclike \nmemory were seen in older transgenic mice, however, in contrast to hippocampal \nactivity, no deficits were reported in young transgenic mice compared to wild-types. \nIn the second section of this thesis the hypothesis that long-term voluntary exercise can reduce cognitive decline was tested. Exercise improved cognition in transgenic, but not wildtype \nmice, in tests of working and reference spatial memory. In addition, a deficit in \nconfigural memory for episodic information was reversed in transgenic mice by exercise. \nThe effect of exercise on amyloid levels and DG neurogenesis was assessed, as these are \nputative molecular substrates which may be altered by exercise leading to improved \ncognition. However, exercise did not significantly influence either of these measures. \nThese data indicate sub-region specific changes in hippocampus network activity in the \nTg2756 model of amyloid pathology, which may underlie deficits in spatial and episodic-like \nmemory. Furthermore, prolonged exercise reduced cognitive decline in this model, and may \nbe a useful therapeutic intervention to prevent or delay the onset of AD in at-risk patients. \nHowever, the precise molecular mechanisms by which exercise exerts its beneficial effect on \nmemory remain to be established.
Author: Alice Marie Palmer
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: Wellcome Trust
OpenAlex ID: W1792545373