Cellular Specificity of the Blood–CSF Barrier for Albumin Transfer across the Choroid Plexus Epithelium

Abstract

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however the exact mechanism remains unknown. We postulate that SPARC is a docking site for albumin, mediating its uptake and transfer by choroid plexus epithelial cells from blood into cerebrospinal fluid (CSF). We used in vivo physiological measurements of transfer of endogenous (mouse) and exogenous (human) albumins, in situ Proximity Ligation Assay (in situ PLA), and qRT-PCR experiments to examine the cellular mechanism mediating protein transfer across the blood–CSF interface. We report that at all developmental stages mouse albumin and SPARC gave positive signals with in situ PLAs in plasma, CSF and within individual plexus cells suggesting a possible molecular interaction. In contrast, in situ PLA experiments in brain sections from mice injected with human albumin showed positive signals for human albumin in the vascular compartment that were only rarely identifiable within choroid plexus cells and only at older ages. Concentrations of both endogenous mouse albumin and exogenous (intraperitoneally injected) human albumin were estimated in plasma and CSF and expressed as CSF/plasma concentration ratios. Human albumin was not transferred through the mouse blood–CSF barrier to the same extent as endogenous mouse albumin, confirming results from in situ PLA. During postnatal development Sparc gene expression was higher in early postnatal ages than in the adult and changed in response to altered levels of albumin in blood plasma in a differential and developmentally regulated manner. Here we propose a possible cellular route and mechanism by which albumin is transferred from blood into CSF across a sub-population of specialised choroid plexus epithelial cells.

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

“…Immunolocalization of SPARC in apical vesicles of mouse choroid plexus epithelial cells and immunolabeling of albumin in multivesicular bodies in sheep choroid plexuses are both consistent with that hypothesis [138]. It would also be consistent with the presence of albumin/SPARC complexes (detected by the in situ proximity ligation assay) in the ependymal and subependymal layer [139]. …”

SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts

“…However, Neesse et al showed that tissue and plasma concentrations of nab -paclitaxel were comparable with those of mouse albumin bound paclitaxel (20). Liddelow et al also showed that human albumin bound mouse SPARC (36). …”

Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect

“…Radiolabeled albumin may also be processed in the body during the experimental period through normal albumin turnover resulting in liberation of radiolabeled amino acids and reincorporation into proteins that are subsequently absorbed into the brain parenchyma [13]. Finally, access of albumin to the CSF has been reported, which may result in some appearance of the radiolabel in the brain [25]. Although any or all of these mechanisms may be responsible for the background albumin levels in control animals, the comparison with CCI-treated animals is compelling and future studies with small molecule drugs may help to discriminate between these effects.…”