Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system.
Extracellular pathways circumventing the mammalian blood-brain fluid barriers (e.g., blood-brain and blood-CSF barriers) have been investigated in the rat by immunohistochemical localization of the endogenous serum proteins albumin, IgG, complement C-9, and IgM and by the exogenous tracer protein horseradish peroxidase (HRP). A demonstrable extracellular pathway into the central nervous system (CNS) is evident at the level of the subarachnoid space/pial surface. Immunoreaction products for the serum proteins and reaction product of intravenously administered HRP are identified over the entire pial surface, in the Virchow-Robin spaces and subpial cortical grey matter, and within phagocytes occupying the subarachnoid space/pial surface and perivascular clefts throughout the CNS. From specific circumventricular organs (e.g., median eminence, area postrema, subfornical organ), well known to lie outside the blood-brain barrier (BBB), each of the blood-borne proteins readily enters adjacent white and grey matter and the ventricular system for subsequent rostrocaudal labeling of the ependymal cell lining. Similar immunohistochemical and blood-borne HRP results are obtained in the CNS of the neonatal rat. Peroxidase delivered into the aorta of postmortem adult rats confirms the presence of a BBB in brain sites containing blood vessels impermeable to blood-borne HRP and the absence of a BBB in sites revealed as leaky to blood-borne HRP in the live rat. The results suggest blood-borne macromolecules, including those of the immune and complement systems, have potential widespread, extracellular distribution within the CNS and cerebrospinal fluid from sites deficient in a BBB (e.g., subarachnoid space/pial surface, circumventricular organs). These observations may have important clinical implications regarding experimental and pathologic autoimmune dysfunction within the CNS and impact on the interpretation of potential transcytosis of blood-borne peptides and proteins through the cerebral endothelium in vivo. A summary diagram of suspected extracellular and intracellular pathways circumventing the blood-brain fluid barriers is provided.
Broadwell
R D
RD
Department of Surgery, University of Maryland School of Medicine, Baltimore 21201.
Sofroniew
M V
MV
D000818:Animals; D000831:Animals, Newborn; D016477:Artifacts; D001798:Blood Proteins / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D002560:Cerebrovascular Circulation; D003186:Complement C9 / Q000032:analysis; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006735:Horseradish Peroxidase / Q000032:analysis / Q000097:blood; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D008955:Models, Cardiovascular; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051381:Rats; D011920:Rats, Inbred WF; D017208:Rats, Wistar; D012709:Serum Albumin / Q000032:analysis
D001798:Blood Proteins; D003186:Complement C9; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012709:Serum Albumin; D006735:Horseradish Peroxidase