Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2

Authors

  • Milène Vandal,

    1. Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada
    2. Institut des Nutraceutiques et des Aliments Fonctionnels, Université Laval, Québec City, Québec, Canada
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  • Wael Alata,

    1. Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada
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  • Cyntia Tremblay,

    1. Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada
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  • Christine Rioux-Perreault,

    1. Centre de recherche sur le vieillissement, Université de Sherbrooke, Sherbrooke, Québec, Canada
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  • Norman Salem Jr,

    1. Nutritional Lipids, DSM Nutritional Products Inc., Columbia, South Carolina, USA
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  • Frédéric Calon,

    Corresponding author
    1. Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada
    2. Institut des Nutraceutiques et des Aliments Fonctionnels, Université Laval, Québec City, Québec, Canada
    • Address correspondence and reprint requests to Mélanie Plourde, Département de médecine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, CSSS-IUGS, Pavillon D'Youville, 1036, rue Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4. E-mail: melanie.plourde2@usherbrooke.ca; Frédéric Calon, Faculté de Pharmacie, Université Laval, Centre de recherche du CHUQ (bur. T-2-05), 2705 boulevard Laurier, Québec, Québec, Canada, G1V 4G2. E-mail: frederic.calon@crchul.ulaval.ca

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  • Mélanie Plourde

    Corresponding author
    1. Institut des Nutraceutiques et des Aliments Fonctionnels, Université Laval, Québec City, Québec, Canada
    2. Centre de recherche sur le vieillissement, Université de Sherbrooke, Sherbrooke, Québec, Canada
    • Address correspondence and reprint requests to Mélanie Plourde, Département de médecine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, CSSS-IUGS, Pavillon D'Youville, 1036, rue Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4. E-mail: melanie.plourde2@usherbrooke.ca; Frédéric Calon, Faculté de Pharmacie, Université Laval, Centre de recherche du CHUQ (bur. T-2-05), 2705 boulevard Laurier, Québec, Québec, Canada, G1V 4G2. E-mail: frederic.calon@crchul.ulaval.ca

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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 [14C]-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 [14C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r2 = 0.21) and AD patients (r2 = 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.

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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).

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