title: Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.
abstract: Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E ε4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [(14) C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4- and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r(2) = 0.21) and AD patients (r(2) = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD).
authors.affiliation: Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada; Institut des Nutraceutiques et des Aliments Fonctionnels, Université Laval, Québec City, Québec, Canada.
authors.forename: Milène
authors.initials: M
authors.lastname: Vandal
authors.forename: Wael
authors.initials: W
authors.lastname: Alata
authors.forename: Cyntia
authors.initials: C
authors.lastname: Tremblay
authors.forename: Christine
authors.initials: C
authors.lastname: Rioux-Perreault
authors.forename: Norman
authors.initials: N
authors.lastname: Salem
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.forename: Mélanie
authors.initials: M
authors.lastname: Plourde
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001692:Biological Transport; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D004281:Docosahexaenoic Acids
keywords: Alzheimer's disease; apolipoprotein E; blood-brain barrier; docosahexaenoic acid; long-chain omega-3 polyunsaturated fatty acids