The Isoform-Specific Pathological Effects of ApoE4 in vivo are Prevented by a Fish Oil (DHA) Diet and are Modified by Cholesterol

Article type: Research Article

Authors: Kariv-Inbal, Zehavit^{a; 1} | Yacobson, Shiri^{a; 1} | Berkecz, Robert^b | Peter, Maria^c | Janaky, Tamas^b | Lütjohann, Dieter^d | Broersen, Laus M.^e | Hartmann, Tobias^f | Michaelson, Daniel M.^{a; *}

Affiliations: [a] The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel | [b] Department of Medical Chemistry, University of Szeged, Szeged, Hungary | [c] Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary | [d] Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany | [e] Danone N. Research Center for Specialized Nutrition, Wagoningen, The Netherlands | [f] Department of Experimental Neurology, Deutsches Institut für Demenzprävention, University of the Saarland, Bad Homburg, Germany

Correspondence: [*] Correspondence to: Daniel M. Michaelson, Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 3 6409624; Fax: +972 3 6407643; E-mail: [email protected].

Note: [1] Both authors contributed equally to the manuscript.

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.

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E4, cholesterol, DHA, GABAergic, glutamatergic

DOI: 10.3233/JAD-2011-111265

Journal: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 667-683, 2012