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Brain membrane aging: functional outcomes and protection by dietary omega-3 polyunsaturated fatty acids

Lipids in Agronomy, Health and Disease : Congres GERLI, 25 octobre - 28 novembre, Strasbourg, France

Colin, J., Huguet, M., Derrien, A., Yen Potin, F., Malaplate-Armand, C., Oster, T.

2015

In the demographic context of the continuously increasing lifespan in Western countries, the rise of chronic diseases related to aging, including Alzheimer’s disease and other dementia types, has become a major public health issue. The chronic impact of many modifiable risk factors and the lack of curative treatments illustrate the need for the development of preventive interventions to minimize the onset of these age-related diseases. The present study focused on the effects of aging and high-fat diet-induced dyslipidemia on the properties of cortical membrane extracted from mouse brain. Our results clearly identified the neuronal membranes as essential biological entities for normal brain function. We showed that aging led to composition and architectural changes in membrane microdomain organization. These changes were associated with the exclusion of CNTF (ciliary neurotrophic factor) receptor subunits from the lipid rafts, resulting in disruption of the associated STAT3 and ERK1/2 signalization pathways. We also observed similar pro-aging type changes in brain membranes of dyslipidemic mice fed a high-fat diet. Such a functional disruption also reduced the neuroprotective responsiveness to CNTF, such as those sought by anti-Alzheimer’s therapies. These data suggested that disturbances of lipid homeostasis could be correlated with increased risk of developing age-related cardiovascular and metabolic as well as neurodegenerative diseases. We finally demonstrated the potential of dietary supplementation with docosahexaenoic acid (C22:6, ?3), the most abundant long-chain polyunsaturated fatty acid in the brain, in preventing CNTF receptor delocalization and disruption, and observed its ability to preserve a neuroprotective response that was impaired in older mice. The results of our study demonstrate the importance of taking into account the aging factor when designing appropriate animal models for a better understanding of the deleterious processes of age-related diseases. Our observations also validate the functional interest of combining pharmacological treatments and preventive nutritional approaches based on polyunsaturated fatty acids ?3 to preserve the neuronal membrane responsiveness in the elderly, in order to minimize brain aging and to optimize the efficiency of anti-Alzheimer’s therapeutic molecules and approaches.

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