Effects of dietary docosahexaenoic acid supplementation on pathology and cognition in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Despite over 100 years of research, there is no cure for the disease. Thus, ways of preventing its onset and/or slowing its progression are of particular interest. Evidence from epidemiological and animal studies has suggested that dietary docosahexaenoic acid (DHA) may reduce the incidence of AD and, more specifically, attenuate P-amyloid (Ap) pathology and improve cognitive symptoms associated with the disease. However, the efficacy of such an intervention remains controversial. Some clinical trials and animal studies have shown limited or no effect of DHA supplementation on behaviour or pathology. Therefore, further research is required to test the hypothesis that dietary DHA supplementation improves cognition and alleviates Ap pathology. The strategy adopted in this thesis was to evaluate dietary DHA supplementation on cognition and pathology in a mouse model of p-amyloid pathology. Tg2576 transgenic mice (Tg), which overexpress the human APPswe mutation, and wild type littermates were fed a diet containing approximately 1.8% DHA or a control diet from the age of 4 months. The mice were tested at different times (8, 12 and 16 months of age) using two different spatial memory tasks. Lipid analyses were carried out on plasma and specific brain regions and the distribution of Ap was analysed using immunohistochemistry and enzyme-linked immunosorbent assay. The results showed that the levels of DHA were increased in plasma and in cortex, hippocampus and cerebellum of DHA-fed mice. In addition, the brain lipid analysis showed that phosphatidylethanolamine (PE), a major phospholipid in brain, was one of the main DHA-containing phospholipids and was the phospholipid that was most clearly affected by dietary DHA and Ap pathology. However, long-term DHA supplementation had only a mild positive effect on learning and memory in the Tg mice. There was no statistically significant effect of DHA supplementation on the accumulation of soluble and insoluble Apl-40 and Apl-42 in the cortex and the hippocampus of Tg mice. These findings suggest that DHA may improve cognitive functions in Tg2576 mice, perhaps by reducing the inflammatory and oxidative effects caused by Ap, rather than reducing the accumulation of the Ap peptide per se and that PE may have a key role in this process