Transcytotic Pathway for Blood-borne Protein Through the Blood-brain Barrier

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The transcytosis of blood-borne protein through the blood-brain barrier, a consequence of recruitment of the Golgi complex within nonfenestrated cerebral endothelia, was identified in mice and rats injected intravenously with the lectin wheat germ agglutinin (WGA) conjugated to the enzymatic tracer horseradish peroxidase (HRP). WGA enters cells by adsorptive endocytosis after binding to specific cell surface oligosaccharides. Blood-borne WGA-HRP labeled the entire cerebrovascular tree from the luminal side 5 min after injection; pericytes, located on the abluminal surface of cerebral endothelia, sequestered the lectin conjugate 6 hr later. Endothelial organelles harboring WGA-HRP 3 hr after injection included the luminal plasmalemma, endocytic vesicles, endosomes (prelysosomes), secondary lysosomes, and the Golgi complex. The peroxidase reaction product labeled the abluminal surface of cerebral endothelia and occupied the perivascular clefts by 6 hr. Within 12 hr, organelles labeled with WGA-HRP in pericytes were identical to those observed in endothelia. Blood-borne native HRP, entering cells by bulk-phase endocytosis, was neither directed to the Golgi complex nor transferred across nonfenestrated cerebral endothelia. The results suggest that blood-borne molecules taken into the cerebral endothelium by adsorptive endocytosis and conveyed to the Golgi complex can, either by themselves or as vehicles for other molecules excluded from the brain, undergo transcytosis through the blood-brain barrier without compromising the integrity of the barrier.

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Proceedings of the National Academy of Sciences of the United States of America





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