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 DHA-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 PPARα agonist clofibrate (100 μM), and PPARβ/δ agonists GW0742 (1 μM) and GW501506 (0.5 μM), did not affect FABP5 protein expression. In contrast, the PPARγ agonists rosiglitazone (5 μM), pioglitazone (25 μM), and troglitazone (1 μM) 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 14C-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 14C-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 PPARγ can regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.

中文翻译：

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吡格列酮增加了脂肪酸结合蛋白5和二十二碳六烯酸贩运进入大脑的血脑屏障表达。

脑中二十碳六碳六烯酸（DHA）（一种必不可少的认知有益脂肪酸）的水平在阿尔茨海默病（AD）中降低。我们已经在AD小鼠模型中证明，这与DHA的血脑屏障（BBB）转运减少和关键DHA转运蛋白，脂肪酸结合蛋白5（FABP5）的表达降低有关。这项研究的重点是评估过氧化物酶体增殖物激活受体（PPAR）同工型对BBB上FABP5表达和功能的影响。使用永生化的人脑内皮细胞（hCMEC / D3），用PPARα激动剂clofibrate（100μM）和PPARβ/δ激动剂GW0742（1μM）和GW501506（0.5μM）处理72小时，不会影响FABP5蛋白的表达。相比之下，PPARγ激动剂罗格列酮（5μM），吡格列酮（25μM），曲格列酮和曲格列酮（1μM）在hCMEC / D3细胞中分别使FABP5蛋白表达增加1.15倍，1.18-和1.24倍，罗格列酮和吡格列酮也增加FABP5的mRNA表达。与FABP5表达的增加相一致，吡格列酮在2分钟内使hCMEC / D3细胞对14C-DHA的摄取增加了1.20-1.33倍，这与参与DHA吸收的膜转运蛋白的表达增加无关。此外，使用原位经心灌注技术，用吡格列酮（40 mg / kg /天，持续7天）治疗雄性C57BL / 6J小鼠，在1分钟内导致14C-DHA的BBB转运增加1.79倍。脑微血管FABP5蛋白表达增加了1.82倍。总体，