Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany.
Nat Commun. 2013;4:2123. doi: 10.1038/ncomms3123.
Loss of folate receptor-α function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-α-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-α-positive exosomes. Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-α-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.
叶酸受体-α 功能丧失与脑叶酸转运缺陷和儿童期发病的神经退行性变有关。为了阐明血脑屏障中脑叶酸转运的机制，我们研究了 5-甲基四氢叶酸在极化细胞中的转运。在这里，我们在多泡体中鉴定了叶酸受体-α 阳性的腔内囊泡，并证明了人类叶酸受体-α和标记的叶酸从基底外侧膜到大鼠脉络丛细胞的顶膜的定向共转运。叶酸受体-α 转染的大鼠脉络丛细胞的顶端培养基和人脑脊液中均含有叶酸受体-α 阳性的外泌体。叶酸受体-α 表达的脑脊液外泌体丢失与 5-甲基四氢叶酸浓度的严重降低相关，这证实了叶酸受体-α 介导的叶酸转运在脑脊液中的重要性。将叶酸受体-α 阳性和阴性外泌体注入小鼠脑室内，证明了外泌体在脑实质中的叶酸受体-α 依赖性递呈。我们的研究结果揭示了一种新的叶酸受体-α 依赖性外泌体介导的叶酸递呈到脑实质的途径，并为大脑药物靶向开辟了新的途径。
