Transcytosis of macromolecules at the blood-brain barrier

The restrictive nature of the blood-brain barrier means that cellular machinery must be in place to deliver macromolecules to the brain. This is achieved by transcytosis which is more complex than initially supposed, both in terms of structure and regulation. Brain endothelial cells have relatively few pinocytotic vesicles compared to peripheral endothelia but can still deliver macromolecules via one of the three main types of vesicles: the most numerous clathrin-coated vesicles containing adaptor protein complex-2, the smaller caveolae formed from lipid raft domains of the plasma membrane, and the large fluid engulfing macropinocytotic vesicles. Both clathrin-coated vesicles and, to a lesser extent caveolae, endocytose plasma membrane receptors and their specific ligands which include insulin, transferrin, and lipoproteins. This receptor-mediated transcytosis (RMT) delivers the ligands to the brain and enables their receptors to be recycled back to the plasma membrane. However, once endocytosed, the ligands and/or receptors must be directed toward the correct plasma membrane and avoid degradation. How this is achieved has not been well studied although there is an important role for Rab GTPases in targeting vesicles to their correct location and enabling exocytosis. In this chapter, we discuss what is known about regulation of transcytosis in related cells such as the MDCK cell line and where are the gaps in our knowledge of brain endothelial transcytotic regulation. We discuss how RMT has been exploited to deliver therapeutic drugs to the brain and the importance of further investigation in this area to improve drug delivery.