Transcellular routes of blood-brain barrier disruption

Abstract

Disruption of the blood-brain barrier (BBB) can occur through different mechanisms and pathways. As these pathways result in increased permeability to different classes of substances, it is likely that the neurological insults that occur will also differ for these pathways. The major categories of BBB disruption are paracellular (between cells) and transcellular (across cells) with a subcategory of transcellular leakage involving vesicles (transcytotic). Older literature, as well as more recent studies, highlights the importance of the transcellular pathways in BBB disruption. Of the various transcytotic mechanisms that are thought to be active at the BBB, some are linked to receptor-mediated transcytosis, whereas others are likely involved in BBB disruption. For most capillary beds, transcytotic mechanisms are less clearly linked to permeability than are membrane spanning canaliculi and fenestrations. Disruption pathways share cellular mechanisms to some degree as exemplified by transcytotic caveolar and transcellular canaliculi formations. The discovery of some of the cellular components involved in transcellular mechanisms of BBB disruption and the ability to measure them are adding greatly to our classic knowledge, which is largely based on ultrastructural studies. Future work will likely address the conditions and diseases under which the various pathways of disruption are active, the different impacts that they have, and the cellular biology that underlies the different pathways to disruption.

Keywords: Blood–brain barrier; adsorptive transcytosis; caveolae; clathrin; disruption; fenestrations; paracellular; transcellular; transcytosis.

Figure 1.

Fenestral construction. Conceptual illustration of the fusion of cell membranes forming the fenestral pore. Diaphragm is not illustrated, but would be a concentric/octagonal opening up to 15 nm in diameter associated with PLVAP. Fenestrae are ringed by cholesterol and cytoskeleton and tend to be clustered into sieve plates that in turn are delimited by microtubules. (A color version of this figure is available in the online journal.)

Figure 2.

Transcellular processes: caveolae and fenestrae. In fenestrated non-brain endothelial cells (a), fenestrae permit leakage of medium-sized molecules. Fenestrae typically express fenestral diaphragms comprised of PLVAP (purple strands) and tufts of heparan sulfate proteoglycan (black), shown in inset. Paracellular junctions of most non-brain endothelial cells are leaky, and permit leakage of small solutes between cells (b). Caveolae contribute to leakage either through formation of transendothelial channels (c), or transcellular vesicular transport (d and e). Caveolar vesicles and transendothelial cell channels can express stomatal diaphragms comprised of PLVAP (purple strands) but that lack heparan tufts (inset, c and d). Caveolae that lack stomatal diaphragms (e) may permit leakage of larger molecules into tissues. In brain endothelial cells, tight junction proteins limit paracellular leakage of substances (f). Fenestrae and caveolar formation is suppressed, in part, by expression of Mfsd2a (blue, g), which transports DHA to the inner leaflet of the endothelial cell plasma membrane which inhibits association of caveolin-1 with the membrane. (A color version of this figure is available in the online journal.)

Figure 3.

Size ranges of various pathways of BBB disruption. Open tight junctions are likely less than 5 nm diameter, but may be up to 20 nm, especially in sinusoidal capillary beds. The functional leakage size (fenestrae with diaphragms and fenestrae without diaphragms) and physical diameter of the entire fenestrae (fenestral pore) are both indicated. Arrows indicate the approximate diameter of several molecules and viruses, illustrating that leakage pathways vary in the size of substance they would permit to cross the BBB. (A color version of this figure is available in the online journal.)