title: The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol.
abstract: Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22 : 6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil diet enriched in DHA and to a cholesterol-containing diet under regular and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA) diet could be used to attenuate the effects of apoE4 in AD.
authors: The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors: Zehavit
authors: Z
authors: Kariv-Inbal
authors: Shiri
authors: S
authors: Yacobson
authors: Robert
authors: R
authors: Berkecz
authors: Maria
authors: M
authors: Peter
authors: Tamas
authors: T
authors: Janaky
authors: Dieter
authors: D
authors: Lütjohann
authors: Laus M
authors: LM
authors: Broersen
authors: Tobias
authors: T
authors: Hartmann
authors: Daniel M
authors: DM
authors: Michaelson
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000178:diet therapy / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D005227:Fatty Acids / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology / Q000235:genetics; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010743:Phospholipids / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D005227:Fatty Acids; D010743:Phospholipids; D020033:Protein Isoforms; D050496:Vesicular Glutamate Transport Proteins; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D004281:Docosahexaenoic Acids; D002784:Cholesterol