ABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by extracellular deposits of fibrillar aggregates of amyloid-beta peptide (Abeta). Levels of docosahexaenoic acid (DHA, 22:6n-3), the major fatty acid component of the neuronal membrane, are reduced in the AD hippocampus. We hypothesized that hippocampal neurons with reduced DHA levels would be more susceptible to aggregated Abeta-induced death and that this might be overcome by increasing hippocampal neuronal DHA levels. Embryonic Day 18 rat hippocampal cells were cultured in neurobasal medium with B27 supplemented with 0-100 microM DHA for 8 days, then were treated with 5 microM aggregated Abeta(42) for 1 day. We found that supplementation with 5-10 microM DHA, which resulted in hippocampal neuron DHA levels of 12-16% of total fatty acids, was optimal for primary hippocampal neuronal survival, whereas supplementation with 5 or 25 microM DHA attenuated aggregated Abeta(42)-induced neurotoxicity and protected hippocampal neurons, with 25 microM DHA being more effective. DHA supplementation also resulted in significant up-regulation of expression of tyrosine tubulin and acetylated tubulin. We suggest that hippocampal neuronal DHA levels may be critical for AD prevention by attenuating the neurotoxicity induced by Abeta and in maintaining hippocampal neuron survival.
Subject(s)
Alzheimer Disease/prevention & control , Amyloid beta-Peptides/antagonists & inhibitors , Cytoskeletal Proteins/metabolism , Docosahexaenoic Acids/administration & dosage , Hippocampus/metabolism , Neuroprotective Agents/administration & dosage , Peptide Fragments/antagonists & inhibitors , Up-Regulation , Acetylation , Alzheimer Disease/chemically induced , Alzheimer Disease/metabolism , Amyloid beta-Peptides/toxicity , Animals , Cell Survival/drug effects , Cells, Cultured , Docosahexaenoic Acids/metabolism , Fatty Acids/metabolism , Hippocampus/drug effects , Hippocampus/embryology , Hippocampus/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/metabolism , Peptide Fragments/toxicity , Rats , Rats, Sprague-Dawley , Time Factors , Tubulin/metabolismABSTRACT
Brain docosahexaenoic acid (DHA, 22:6n-3) levels are associated with learning memory performance, but it is not known the mechanism of DHA on enhancing memory effect. The aim of this study was to examine effect of brain DHA levels on cytoskeleton expression. Rats were fed a chow or sunflower oil-based n-3 fatty acid-deficient diet supplemented with or without fish oil starting from embryo and through postnatal day 140. The various DHA levels were from 5.0% to 15.6% of total fatty acids in hippocampus, 3.9% to 13.7% in visual cortex, and 5.3% to 14.4% in olfactory bulbs. The expression of the cytoskeleton markers tyrosine tubulin, acetylated tubulin, and beta-actin in the hippocampus, visual cortex and olfactory bulb was not affected by brain DHA levels.
Subject(s)
Brain/drug effects , Cytoskeleton/metabolism , Docosahexaenoic Acids/pharmacology , Learning/drug effects , Memory/drug effects , Animals , Brain/metabolism , Dietary Fats, Unsaturated/administration & dosage , Dietary Fats, Unsaturated/pharmacology , Dose-Response Relationship, Drug , Female , Fish Oils , Gene Expression , Learning/physiology , Memory/physiology , Plant Oils , Pregnancy , Random Allocation , Rats , Rats, Sprague-Dawley , Sunflower Oil , Tubulin/metabolismABSTRACT
Most previous studies have focused on improved reference memory and recovery of whole brain docosahexaenoic acid [DHA, 22:6(n-3)] levels in DHA-deficient animals supplemented with fish oil (FO) or switched to an adequate DHA-enriched diet. The aims of this study were to determine whether reference and working memory performance can be enhanced in control male rats and improved in (n-3) fatty acid-deficient male rats given an FO supplement and whether brain DHA accumulation, deficiency, and recovery are region specific. From the embryo to postnatal d 140, 4 groups of rats were fed a nonpurified or sunflower oil-based (n-3) fatty acid-deficient diet alone or supplemented with (n-3) fatty acids from FO representing approximately 0.3% of the energy source. The male rats were tested at postnatal d 102-130 for spatial learning memory performance in the Morris water maze. The fatty acid composition of different brain regions was analyzed by GC. Rats fed the (n-3) fatty acid-deficient diet showed significantly poorer reference and working memory, and FO supplementation partially rescued both memory performances. Furthermore, FO supplementation during brain development and adulthood in normal rats resulted in significant enhancement of both memories. Following dietary DHA repletion, the hippocampus and olfactory bulbs accumulated more DHA, were more resistant to dietary DHA deprivation, and showed better DHA recovery than the visual cortex, frontal cortex, and cerebellum. These results suggest that DHA is critical for the development and maintenance of learning memory performance.
