Pathways into, through, and around the fluid-brain barriers

The potential intracellular and extracellular pathways that blood-borne substances may follow for circumventing the fluid-brain barriers and entry to the CNS are numerous. The extracellular avenues, patent to blood-borne protein the size of IgM, and movement of blood-borne macromolecules through perivascular clefts deep into the CNS complicate the interpretation and identification of bona fide transcytosis through the BBB. The often-stated belief in literature reviews of the BBB that nonfenestrated cerebral endothelia fail to engage in endocytosis and possess few vesicles under normal conditions is invalid. Endocytic vesicle formation and vesicular traffic among constituents of the endomembrane system are no different in BBB endothelia than in other cell types. Available biochemical and morphological data advocate the transcytosis of blood-borne protein and peptides through nonfenestrated cerebral endothelia. However, absence of demonstrable endocytic activity at the abluminal front compared with a very prominent endocytic activity at the luminal surface of BBB endothelia argues against bidirectional membrane trafficking through the BBB and supports the concept of a brain-blood barrier. The latter is no less significant functionally than the BBB and may be more so in deterring transendothelial transfer of peptides and proteins bidirectionally through the nonfenestrated cerebral endothelium. The difficulty in interpreting transcytosis through BBB endothelia is not encountered for epithelia of the blood-CSF barrier at the level of the choroid plexus. Choroid epithelia engage in endocytosis circumferentially; hence, the potential for transcytosis and circumvention of the blood-CSF barrier through an intraepithelial route exists bidirectionally in the choroid plexus.