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Neurobiology of Disease 16 (2004) 1 13
Introduction
The blood brain barrier (BBB) is a diffusion barrier essential
for the normal function of the central nervous system. The BBB
endothelial cells differ from endothelial cells in the rest of the body
by the absence of fenestrations, more extensive tight junctions
(TJs), and sparse pinocytic vesicular transport. Endothelial cell
tight junctions limit the paracellular flux of hydrophilic molecules
across the BBB. In contrast, small lipophilic substances such as O2
* Corresponding author. Neonatal Intensive Care Unit, 2nd Floor, Main
Building, Westchester Medical Center, Valhalla, NY 10595. Fax: +1-914594-4453.
E-mail address: pballabh@msn.com (P. Ballabh).
Available online on ScienceDirect (www.sciencedirect.com.)
0969-9961/$ - see front matter D 2004 Published by Elsevier Inc.
doi:10.1016/j.nbd.2003.12.016
Fig. 1. Blood brain barrier and the tight junction. (A) Schematic drawing of the blood brain barrier in transverse section showing endothelium, basement
membrane, pericytes, astrocytes, and tight junctions. The localization of gap junction, GFAP, and aquaporin-4 are shown. (B) Electron micrograph of
mammalian blood brain barrier showing endothelial tight junction. [Adapted from: The Blood Brain Barrier Cellular and Molecular Biology. Pardridge,
W.M. (Ed.). Raven Press]. (C) Schematic representation of protein interaction associated with tight junctions at the blood brain barrier. Claudin, occludin, and
junction adhesion molecule are the transmembrane proteins, and ZO-1, ZO-2, and ZO-3, cingulin, and others are the cytoplasmic proteins. Claudins are linked
to actins through intermediary cytoplasmic proteins.
Occludin
Occludin was identified in 1993 as the first integral protein
localized at the TJ by immunogold freeze fracture microscopy in
chickens (Furuse et al., 1993) and then in mammals (AndoAkatsuka et al., 1996). It is a 65-kDa phosphoprotein, significantly
larger than claudin. Occludin shows no amino acid sequence
similar to the claudins. Occludin has four transmembrane domains,
a long COOH-terminal cytoplasmic domain, and a short NH2terminal cytoplasmic domain. The two extracellular loops of
occludin and claudin originating from neighboring cells form the
paracellular barrier of TJ. The cytoplasmic domain of occludin is
directly associated with ZO proteins. The expression of occludin
has also been documented in rodents (Hirase et al., 1997) and adult
human brain (Papadopoulos et al., 2001) but not in normal human
newborn and fetal brain. Occludin expression is much higher in
brain endothelial cells compared to nonneural tissues. Occludin
appears to be a regulatory protein that can alter paracellular
permeability (Hirase et al., 1997).
Fig. 2. Claudin-5 (red in A) and GFAP (white in B) immunolabeling of cerebral blood vessels of a term newborn. This infant with cardiomyopathy died in our
neonatal intensive care unit on day 2 of life. Coronal section of frontal cortex was immunostained with claudin-5 and GFAP in our laboratory. Claudin-5 is
strongly expressed in blood vessels. Astrocyte end-feet, visualized by GFAP-staining, closely cover the blood vessels. Colocalization by double-labeling of
claudin-5 and GFAP (Fig. 3C). Scale bar = 20 Am.
endothelial cell monolayers that are cultured in astrocyte-conditioned media, suggesting that an astrocyte-derived soluble factor
may be responsible for induction of BBB characteristics in endothelial cells (Neuhaus et al., 1991).
However, subsequent investigators criticized the culture and
transplantation experiments on methodologic grounds and also
disagreed with the view that mature astrocytes play a significant
role in the initial expression of the BBB (Holash et al., 1993). It
was reported that intact neuronal or glial cells were not necessary
for the maintenance of the BBB properties (Krum et al., 1997).
They induced neuronal and glial injury by injecting immunotoxin
OX7-SAP and the ribosome-inactivating protein saporin into the
adult rat striatum. The microvasculature was noted to be intact,
allowing a qualitative immunohistochemical analysis of several
BBB markers at time points ranging from 3 to 28 days postinjection (Krum et al., 1997). These contradictions may be resolved
by additional experiments using host animals of different ages,
standard grafting methodology, and systematic analysis of grafts
after vascularization. The role of astrocytes in the formation of
the BBB is of great interest to scientists and may have therapeutic
implications.
Fig. 3. Aquaporin-4 (A) and laminin (B) expression in cerebral blood vessel of a term human newborn. Coronal section of cerebral cortex (frontal lobe)
immunostained in our laboratory for aquaporin-4 and laminin. (A) Aquaporin-4-staining of astrocyte end-feet seems to be continuous. (B) Laminin stains the
basement membrane of the blood vessels. (C) Colocalization of aquaporin-4 and laminin. Laminin expression is on luminal side, and aquaporin-4 labels the
astrocyte end-feet covering the blood vessels. Scale bar = 50 Am.
Clinical implications
Fig. 4. Intraventricular hemorrhage. Coronal sections of the brain of a premature newborn of 26 weeks of gestational age who died in our neonatal intensive
care unit. Lateral ventricles are filled with blood and are mildly dilated (A and B).
10
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