Figure 3.

Schematic representation of transport pathways across the blood-cerebrospinal fluid barrier. The blood-cerebrospinal fluid (CSF) barrier is formed by tight junctions between neighboring choroid plexus epithelial cells—halting the paracellular movement of molecules both into, and out of, the brain. Additional chemical barriers exist to impede movement of molecules into the central nervous system. 1–Diffusion for hydrophilic molecules through a paracellular pathway is halted by tight junctions (TJ) between adjacent choroid plexus epithelial cells. 2–Efflux transporters (e.g., ABC family) actively remove specific (mostly) lipophilic solutes from cell cytoplasm and extracellular space. Though the majority of evidence suggests a basolateral removal of molecules to the blood space, there is some evidence that ABCB1 (PGP) and ABCG2 (BCRP) localize to the apical membrane of the choroid plexus (Rao et al., 1999; Gao and Meier, 2001; Gazzin et al., 2008; Niehof and Borlak, 2009; Ek et al., 2010; Reichel et al., 2011), however their function in this position is unknown. 3–Inward transporters (e.g., SLC family) actively transport ions, amino acids, and other small molecules across both basolateral and apical surfaces of plexus epithelial cells into the CSF. Without this active transport these molecules would be unable to cross the blood–CSF barriers as they are too hydrophilic and/or highly polarized. 4–Bi-directional transporters (e.g., OAT family). 5–Protein transporters (e.g., SPARC for albumin) specifically target individual proteins (or classes of protein) and transport them across the cells. 6–Vesicular transport/endocytosis due to presence of specific receptors (e.g., transthyretin receptor, TTR; insulin receptor, INSR) or non-specific mediators (e.g., vesicle-associated membrane proteins, VAMPs). 7–Bulk water flow from blood to CSF via aquaporin transporters, specifically AQP1 (Johansson et al., 2005).