Effect of a high fat diet on a mouse model of Alzheimer's disease

THE UNIVERSITY OF MANCHESTER Abstract of thesis Submitted by Elysse Knight for the degree of Doctor of Philosophy and entitled Effect of a high fat diet on a mouse model of Alzheimer? s disease, December 2010. Alzheimer? s disease (AD) is a progressive neurodegenerative disorder, characterised by deficits in language, behaviour and memory. Increasing evidence suggests that mid-life obesity and a diet high in fat are risk factors for AD. In contrast, life-threatening weight loss occurs and worsens as the disease progresses, despite adequate or increased food intake. A greater understanding of energy balance in AD may therefore uncover novel targets for therapy. The aim of this thesis was to test the hypothesis that 3xTgAD mice display altered energy balance and that experimental changes to this balance will alter cognition. To address this hypothesis, three key objectives were set up; to characterise the energy balance profile, characterise behaviour and memory, and evaluate the response to an high fat (HF) diet in a triple transgenic (3xTgAD) model, an experimental mouse model of AD. Energy balance was characterised in non-transgenic (Non-Tg) control and 3xTgAD mice, demonstrating altered body weight, food intake and metabolic rate in the 3xTgAD mouse model of AD. At 2-month of age male 3xTgAD mice displayed greater food intake and body weight, but no difference in metabolic rate, whereas from 12 months of age 3xTgAD mice weighed less, despite eating more, and had a higher metabolic rate than Non-Tg control mice. This provides evidence that there is a shift towards a hypermetabolic state from 12 months of age in 3xTgAD mice, which may represent a key stage in advancement of the disease process. Behaviour and memory were characterised in Non-Tg control and 3xTgAD mice in a battery of tests at different ages. 3xTgAD mice showed changes in open-field activity/anxiety from 3 months of age. Memory impairments were first detected in 3xTgAD mice at 3 months of age as deficits in odour recognition memory, mirroring early impairments seen in AD patients. Deficits in spatial memory were then observed in both the Y-maze spontaneous alternation and Morris water maze tests from 5 months of age. Finally, deficits in non-spatial visual object memory were observed in 3xTgAD mice in the novel object recognition test at 8 months of age. Energy balance, behaviour and memory were assessed in Non-Tg control and 3xTgAD mice in response to an HF diet. Non-Tg control and 3xTgAD mice displayed similar energy balance profiles in response to an HF diet. The HF diet was found to worsen memory in Non-Tg mice in odour recognition at 3-4 and 7-8 months of age, in the Morris water maze at 7-8 months of age and in novel object recognition and spontaneous alternation at 11-12 and 15-16 months of age. Similarly, the HF diet worsened memory in 3xTgAD mice in odour discrimination at 3-4 and 7-8 months of age, the Morris water maze at 7-8 and 11-12 months of age, and in spontaneous alternation at 15-16 months of age. As an HF diet induced memory impairments, in both Non-Tg control and 3xTgAD mice, it suggests that diet-induced deficits may therefore, not be specific to AD, but rather to cognition in general. Overall, these data demonstrate that 3xTgAD mice show AD-like age-dependent changes in energy balance, behaviour and memory. Furthermore, an HF diet produced impairments in memory in 3xTgAD mice, but these effects were not specific to AD, as an HF diet also led to deficits in control animals. These data support a role for energy balance in the progression of AD, although the underlying mechanisms remain poorly understood. 3xTgAD mice may therefore represent a good model to examine energy balance during AD and to evaluate targets for future therapies.