Docosahexaenoic and eicosapentaenoic acids differentially enhance the blood-brain barrier function via distinct PPAR-dependent upregulation of tight junction proteins in brain endothelial cells.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated omega-3 fatty acids that reduce the risk of Alzheimer's disease and dementia by protecting blood-brain barrier (BBB) function. However, the mechanisms through which DHA and EPA regulate BBB function remain unclear. DHA and EPA act as ligands for the peroxisome proliferator-activated receptor (PPAR), which is a nuclear receptor superfamily member, with three isoforms: α, β, and γ. Tight junctions (TJs) formed between brain endothelial cells play a central role in restricting the paracellular passage of substances across the BBB. In this study, we aimed to investigate whether DHA and EPA regulate TJ protein expression via PPARs. Primary cultured rat brain endothelial cells (RBECs) isolated from Wistar rats were used for in vitro analysis. TJ protein (ZO-1, occludin, and claudin5) and PPARα, β, and γ expression levels in RBECs were measured using western blot analysis. Additionally, to verify PPAR involvement in TJ protein expression regulation, RBECs were treated with DHA or EPA in combination with PPARα, β, or γ inhibitors. The DHA-induced ZO-1 upregulation was suppressed by PPARβ inhibition. Either PPARβ or PPARγ inhibition suppressed the DHA-induced occludin increase, whereas both PPAR inhibitors suppressed the DHA-induced claudin-5 increase. In contrast, the EPA-induced increase in claudin-5 expression was suppressed via PPARγ inhibition. Conclusively, DHA and EPA regulate TJ protein expression via different PPARs in brain endothelial cells, revealing potential targets for the prevention or treatment of neurodegenerative diseases.