Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal.

A critical appraisal is presented of nearly two decades of research publications and review articles advocating the bidirectional transcytosis of fluid-phase molecules, most notably native horseradish peroxidase (HRP), through the normal and experimentally modified blood-brain barrier (BBB). Extracellular routes circumventing the BBB in normal and pathological states and artifact introduced in histological preparation of CNS tissue exposed to blood-borne peroxidase are emphasized. The potential for transcytosis of macromolecules entering the nonfenestrated cerebral endothelium by the processes of non-specific fluid phase endocytosis (e.g., HRP), adsorptive endocytosis (e.g., lectins) and receptor-mediated endocytosis (e.g., ligands) is analyzed in the context of the cellular secretory process and the complimentary events of endocytosis and exocytosis at the luminal and abluminal plasma membranes. Available data suggest that the cerebral endothelium is polarized with regard to endocytosis and the internalization of cell surface membrane; hence, the transcytosis of specific macromolecules through the BBB may be vectorial. If these data are correct, the blood-brain barrier is not absolute, whereas its counterpart, the brain-blood barrier, may be.