Pioglitazone Increases Blood-Brain Barrier Expression of Fatty Acid-Binding Protein 5 and Docosahexaenoic Acid Trafficking into the Brain

Brain levels of docosahexaenoic acid (DHA), an essential cognitively beneficial fatty acid, are reduced in Alzheimer's disease (AD). We have demonstrated in an AD mouse model that this is associated with reduced blood-brain barrier (BBB) transport of DHA and lower expression of the key DMA-trafficking protein, fatty acid-binding protein 5 (FABP5). This study focused on assessing the impact of activating peroxisome proliferator-activated receptor (PPAR) isoforms on FABP5 expression and function at the BBB. Using immortalized human brain endothelial (hCMEC/D3) cells, a 72 h treatment with the PPAR alpha agonist clofibrate (100 mu M), and PPAR beta/delta agonists GW0742 (1 mu M) and GW501506 (0.5 mu M), did not affect FABP5 protein expression. In contrast, the PPAR gamma agonists rosiglitazone (5 mu M), pioglitazone (25 mu M), and troglitazone (1 mu M) increased FABP5 protein expression by 1.15-, 1.18-, and 1.24-fold in hCMEC/D3 cells, respectively, with rosiglitazone and pioglitazone also increasing mRNA expression of FABP5. In line with an increase in FABP5 expression, pioglitazone increased C-14-DHA uptake into hCMEC/D3 cells 1.20- to 1.33-fold over a 2 min period, and this was not associated with increased expression of membrane transporters involved in DHA uptake. Furthermore, treating male C57BL/6J mice with pioglitazone (40 mg/kg/day for 7 days) led to a 1.79-fold increase in BBB transport of C-14-DHA over 1 min, using an in situ transcardiac perfusion technique, which was associated with a 1.82-fold increase in brain microvascular FABP5 protein expression. Overall, this study demonstrated that PPAR gamma can regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.