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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

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

Glucosamine hydrochloride but not chondroitin sulfate prevents cartilage degradation and inflammation induced by interleukin-1α in bovine cartilage explants

Objective Glucosamine hydrochloride (GH) and chondroitin sulfate (CS) are commonly used for the treatment of osteoarthritis (OA). The aim of this study was to assess their effects, alone and in combination, on preventing aggrecan degradation and inflammation in an in vitro model of OA. Design To test the effects of GH and/or CS as a preventative treatment, cartilage explants were pretreated with the compound(s) using concentrations that showed no detrimental effect on chondrocyte viability. Interleukin-1α (IL-1α) was added to induce cartilage degradation, supernatant and explants were analyzed for proteoglycan degradation products, aggrecanase mRNA expression and activity, and for the release of inflammatory markers. Results Following treatment with IL-1α, 2 mg/mL dose of GH pretreatment was associated with a reduction of glycosaminoglycan release, reduced generation of the pathological interglobular domain aggrecan catabolites, decreased mRNA levels of ADAMTS-4 and -5 and reduced activity of ADAMTS-4. In contrast, CS alone did not have a significant effect on IL-1α-induced cartilage degradation and the addition of 0.4 mg/mL CS to 2 mg/mL GH did not further inhibit IL-1α-induced activity. Pretreatment with 2 mg/mL GH also reduced the release of inflammatory markers, prostaglandin E2 and nitric oxide induced by IL-1α while CS did not have a significant effect. Conclusions The results suggest that GH prevents cartilage degradation mediated by aggrecanases ADAMTS-4 and -5, and may also reduce inflammation. This could be part of the mechanisms by which GH is effective in maintaining joint integrity and function, and preventing or delaying early symptoms of OA

The role of n-3 dietary polyunsaturated fatty acids in brain function and ameliorating Alzheimer's disease: Opportunities for biotechnology in the development of nutraceuticals

Prospective epidemiological surveys and numerous animal studies have shown an important role for dietary docosahexaenoic acid (DHA) in healthy brain function and reducing the risk of dementia. The evidence for this is summarised and some further experiments of our own are described. For the experimentation we have used the Tg2576 mouse, which is a well known model of amyloid pathology and cognitive impairment as seen in Alzheimer's disease. We found that, while brain levels of DHA showed a positive correlation with behaviour and a negative correlation with insoluble β-amyloid (1-40), the general benefits of DHA-enriched diets were not as great as have sometimes been reported in the literature. This may be due to either the age of the animals we tested and/or the fact that we examined the effects of DHA supplementation against a normal healthy control diet condition, unlike previous studies, in order to mimic dietary supplement use in the human population. In addition, we point to some ways in which biotechnology could be used to supplement the world's supply of omega-3 PUFAs (especially DHA) since there is an increasing shortage of such compounds for dietary consumption