20 research outputs found
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
Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease
Alzheimer's disease (AD) is of major concern in ageing populations and we have used the Tg2576 mouse model to understand connections between brain lipids and amyloid pathology. Because dietary docosahexaenoic acid (DHA) has been identified as beneficial, we compared mice fed with a DHA-supplemented diet to those on a nutritionally-sufficient diet. Major phospholipids from cortex, hippocampus and cerebellum were separated and analysed. Each phosphoglyceride had a characteristic fatty acid composition which was similar in cortex and hippocampus but different in the cerebellum. The biggest changes on DHA-supplementation were within ethanolamine phospholipids which, together with phosphatidylserine, had the highest proportions of DHA. Reciprocal alterations in DHA and arachidonate were found. The main diet-induced alterations were found in ethanolamine phospholipids, (and included their ether derivatives), as were the changes observed due to genotype. Tg mice appeared more sensitive to diet with generally lower DHA percentages when on the standard diet and higher relative proportions of DHA when the diet was supplemented. All four major phosphoglycerides analysed showed age-dependent decreases in polyunsaturated fatty acid contents. These data provide, for the first time, a detailed evaluation of phospholipids in different brain areas previously shown to be relevant to behaviour in the Tg2576 mouse model for AD. The lipid changes observed with genotype are consistent with the subtle alterations found in AD patients, especially for the ethanolamine phospholipid molecular species. They also emphasise the contrasting changes in fatty acid content induced by DHA supplementation within individual phospholipid classes
The effects of long-term saturated fat enriched diets on the brain lipidome
The brain is highly enriched in lipids, where they influence neurotransmission, synaptic plasticity and inflammation. Non-pathological modulation of the brain lipidome has not been previously reported and few studies have investigated the interplay between plasma lipid homeostasis relative to cerebral lipids. This study explored whether changes in plasma lipids induced by chronic consumption of a well-tolerated diet enriched in saturated fatty acids (SFA) was associated with parallel changes in cerebral lipid homeostasis. Male C57Bl/6 mice were fed regular chow or the SFA diet for six months. Plasma, hippocampus (HPF) and cerebral cortex (CTX) lipids were analysed by LC-ESI-MS/MS. A total of 348 lipid species were determined, comprising 25 lipid classes. The general abundance of HPF and CTX lipids was comparable in SFA fed mice versus controls, despite substantial differences in plasma lipid-class abundance. However, significant differences in 50 specific lipid species were identified as a consequence of SFA treatment, restricted to phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkyl-PC, alkenyl-PC, alkyl-PE, alkenyl-PE, cholesterol ester (CE), diacylglycerol (DG), phosphatidylinositol (PI) and phosphatidylserine (PS) classes. Partial least squares regression of the HPF/CTX lipidome versus plasma lipidome revealed the plasma lipidome could account for a substantial proportion of variation. The findings demonstrate that cerebral abundance of specific lipid species is strongly associated with plasma lipid homeostasis
N-3 Polyunsaturated Fatty Acids and the Resolution of Neuroinflammation
In the past few decades, as a result of their anti-inflammatory properties, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), have gained greater importance in the regulation of inflammation, especially in the central nervous system (in this case known as neuroinflammation). If sustained, neuroinflammation is a common denominator of neurological disorders, including Alzheimer's disease and major depression, and of aging. Hence, limiting neuroinflammation is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 LC-PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators (SPMs) such as resolvins, maresins and protectins. These SPMs are crucially involved in the resolution of inflammation. They could be good candidates to resolve brain inflammation and to contribute to neuroprotective functions and could lead to novel therapeutics for brain inflammatory diseases. This review presents an overview 1) of brain n-3 LC-PUFAs as precursors of SPMs with an emphasis on the effect of n-3 PUFAs on neuroinflammation, 2) of the formation and action of SPMs in the brain and their biological roles, and the possible regulation of their synthesis by environmental factors such as inflammation and nutrition and, in particular, PUFA consumption
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
Brief intraperitoneal radioimmunotherapy of small peritoneal carcinomatosis using high activities of noninternalizing 125I-labeled monoclonal antibodies.
International audienceThe efficiency, low toxicity, and high tumor-to-healthy tissue uptake ratio associated with brief intraperitoneal (125)I-35A7 radioimmunotherapy suggest that this method can be used in combination with radiation-synergistic drugs in the therapy of small-volume peritoneal carcinomatosis after cytoreductive surgery
Inspired by lipids: the Morton Lecture Award Presentation
Lipids are key molecules for membranes, energy storage and signalling. I have been privileged to have worked in such a diverse field and in organisms from microbes to humans. Here I will describe some of those contrasting areas which range from environmental impacts to food production and on to human health. It has been a fascinating journey which still continues to excite me