Neural networks in a mouse model of amyloid pathology

Palmer, Alice Marie 2012. Neural networks in a mouse model of amyloid pathology. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases. However, the aetiology of AD is still unclear and there is currently no cure. In order to develop new therapeutic strategies more basic research into the underlying mechanisms leading to cognitive impairment is needed. This thesis uses the Tg2576 mouse model to examine the effects of amyloid pathology on hippocampal network activity and memory, and to assess the therapeutic effects of exercise as a lifestyle intervention against amyloid-induced cognitive decline. The hippocampal network is made up of different structural sub-regions, dentate gyrus (DG), CA1 and CA3, each of which plays a different role in memory encoding and retrieval. An analysis of c-fos expression was carried out followed by structural equation modelling to assess neural activity in each sub-region when Tg2576 and wild-type control mice explored a novel or familiar spatial environment. In young transgenic mice there was a reduction in DG engagement when encoding spatial novelty compared to controls. In aged mice deficits in DG engagement were seen in both genotypes. The influence of amyloid-induced hippocampal network alterations on cognition was assessed on a novel task designed to test configural integration of cues relating to episodic memory. An analysis of c-fos expression in normal mice revealed that this task was also DG dependent. Marked deficits in episodiclike memory were seen in older transgenic mice, however, in contrast to hippocampal activity, no deficits were reported in young transgenic mice compared to wild-types. In 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 mice, in tests of working and reference spatial memory. In addition, a deficit in configural memory for episodic information was reversed in transgenic mice by exercise. The effect of exercise on amyloid levels and DG neurogenesis was assessed, as these are putative molecular substrates which may be altered by exercise leading to improved cognition. However, exercise did not significantly influence either of these measures. These data indicate sub-region specific changes in hippocampus network activity in the Tg2756 model of amyloid pathology, which may underlie deficits in spatial and episodic-like memory. Furthermore, prolonged exercise reduced cognitive decline in this model, and may be a useful therapeutic intervention to prevent or delay the onset of AD in at-risk patients. However, the precise molecular mechanisms by which exercise exerts its beneficial effect on memory remain to be established.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Psychology
Subjects:	B Philosophy. Psychology. Religion > BF Psychology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Funders:	Wellcome Trust
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:08
URI:	https://orca.cardiff.ac.uk/id/eprint/40317

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