Molecular transfer across blood-cerebrospinal fluid interface in early brain development

© 2011 Dr. Shane Antony LiddelowThe choroid plexus is the site of the blood-cerebrospinal fluid barrier and restricts the exchange of molecules between the two compartments. The normal development of the lateral ventricular plexus was studied in neonatal opossum (Monodelphis domestica) using BrdU labelling. Results show that choroid plexus cells arise from the neuroependymal wall of the ventricles, with new epithelial cells only added to the structure on the dorsal (upper) side. Plexus cells are long-lived and no apoptosis was seen, even in senescent animals. Early in development cerebrospinal fluid (CSF) contains very high concentrations of protein, most likely generated by transfer from plasma across choroid plexus epithelial cells. Results showed that about 5–10% of plexus epithelial cells are involved in unidirectional transfer of plasma proteins from blood to CSF; about 0.5% of cells transfer passive markers bidirectionally, and a small percentage of cells transfer both. The specificity of the protein transfer was greatest in younger animals and decreased with age. Physiological control of protein transfer across plexus epithelial cells was investigated by injecting adult plasma into Monodelphis pups at different postnatal ages. Concentrations of total and individual plasma proteins were estimated and volumes of the lateral ventricular system measured. Injections of adult plasma resulted in increased total protein concentration in the CSF within 6–24 hours in older, but not younger animals due to ventricular expansion at early ages only. Protein content in CSF increased at all ages. The concentration of individual proteins was differentially altered and numbers of choroid plexus cells immunopositive for them mirrored these changes. Injection of a foreign protein, bovine fetuin, resulted in an increase in CSF protein content and the exogenous protein was detected both in the CSF and within protein-transferring plexus cells. Further investigation of the molecular basis of this transfer was conducted using a microarray screen of E15 and adult mouse lateral ventricular choroid plexus. Comparison of datasets revealed many genes that were differentially expressed, including numerous receptor and protein transporters. One putative plasma protein receptor, osteonectin, was localized to the basolateral (blood) side of the choroid plexus epithelial cells. These combined results suggest that specific transporters responsible for protein transfer at the blood/CSF barrier may be present, raising the possibility of designing specific macromolecular delivery systems into the brain via the choroid plexus epithelial cells and the CSF, especially during development