Brain Transport of Docosahexaenoic Acid Across the Blood–Brain Barrier Decreases in Middle-Aged and Aged Mice

Abstract Background: Nutrients are actively taken up by the brain via various transporters at the blood–brain barrier (BBB). A lack of specific nutrients in the aged brain, including decreased levels of docosahexaenoic acid (DHA), is associated with memory and cognitive dysfunction. To compensate for decreased brain DHA, orally supplied DHA must be transported from the circulating blood to the brain across the BBB through transport carriers including major facilitator superfamily domain-containing protein 2a (MFSD2A) and fatty acid-binding protein 5 (FABP5) that transport esterified and non-esterified DHA, respectively. Although it is known that the integrity of the BBB is altered during aging, the impact of aging on DHA transport across the BBB has not been fully elucidated. Methods: We used 2-, 8-, 12-, and 24-month-old male C57BL/6 mice to evaluate brain uptake of [14C]DHA, as the non-esterified form, using an in situ transcardiac brain perfusion technique. Primary culture of rat brain endothelial cells (RBECs) was used to evaluate the effect of siRNA-mediated MFSD2A knockdown on cellular uptake of [14C]DHA.Results: We found that brain uptake of [14C]DHA was inhibited by excess unlabeled DHA in 2-month-old mice. Transfection of MFSD2A siRNA into RBECs decreased the MFSD2A protein expression levels by 30% and reduced cellular uptake of [14C]DHA by 20%. Twelve- and 24-month-old mice exhibited significant reductions in brain uptake of [14C]DHA and decreased MFSD2A protein expression in the brain microvasculature compared with 2-month-old mice; nevertheless FABP5 protein expression was up-regulated with age. Conclusions: We demonstrated that MFSD2A is involved in non-esterified DHA transport at the BBB. The middle-aged and aged brain has decreased DHA transport across the BBB due to age-related down-regulation of MFSD2A rather than that of FABP5.