Fatty acid-binding protein 5 at the blood–brain barrier regulates endogenous brain docosahexaenoic acid levels and cognitive function

Fatty acid-binding protein 5 (FABP5) at the blood–brain barrier contributes to the brain uptake of docosahexaenoic acid (DHA),a blood-derived polyunsaturated fatty acid essential for maintenance of cognitive function. Given the importance of DHA in cognition,the aim of this study was to investigate whether deletion of FABP5 results in cognitive dysfunction and whether this is associated with reduced brain endothelial cell uptake of exogenous DHA and subsequent attenuation in the brain levels of endogenous DHA. Cognitive function was assessed in male and female FABP5^+/+ and FABP5^-/- mice using a battery of memory paradigms. FABP5^-/- mice exhibited impaired working memory and short-term memory,and these cognitive deficits were associated with a 14.7 ± 5.7% reduction in endogenous brain DHA levels. The role of FABP5 in the blood–brain barrier transport of DHA was assessed by measuring¹⁴C-DHA uptake into brain endothelial cells and capillaries isolated from FABP5^+/+ and FABP5^-/- mice. In line with a crucial role of FABP5 in the brain uptake of DHA,¹⁴C-DHA uptake into brain endothelial cells and brain capillaries of FABP5^-/- mice was reduced by 48.4 ± 14.5% and 14.0 ± 4.2%,respectively,relative to those of FABP5^+/+ mice. These results strongly support the hypothesis that FABP5 is essential for maintaining brain endothelial cell uptake of DHA,and that cognitive deficits observed in FABP5^-/- mice are associated with reduced CNS access of DHA.