Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis.
In multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), dysfunction of the blood-brain barrier (BBB) leads to edema formation within the central nervous system. The molecular mechanisms of edema formation in EAE/MS are poorly understood. We hypothesized that edema formation is due to imbalanced water transport across the BBB caused by a disturbed crosstalk between BBB endothelium and astrocytes. Here, we demonstrate at the light microscopic and ultrastructural level, the loss of polarized localization of the water channel protein aquaporin-4 (AQP4) in astrocytic endfeet surrounding microvessels during EAE. AQP4 was found to be redistributed over the entire astrocytic cell surface and lost its arrangement in orthogonal arrays of intramembranous particles as seen in the freeze-fracture replica. In addition, immunostaining for the astrocytic extracellular matrix receptor beta-dystroglycan disappeared from astroglial membranes in the vicinity of inflammatory cuffs, whereas immunostaining for the dystroglycan ligands agrin and laminin in the perivascular basement membrane remained unchanged. Our data suggest that during EAE, loss of beta-dystroglycan-mediated astrocyte foot process anchoring to the basement membrane leads to loss of polarized AQP4 localization in astrocytic endfeet, and thus to edema formation in EAE.
Wolburg-Buchholz
Karen
K
Institute of Pathology, University of Tübingen, Liebermeisterstrasse 8, 72076 Tübingen, Germany.
Mack
Andreas F
AF
Steiner
Esther
E
Pfeiffer
Friederike
F
Engelhardt
Britta
B
Wolburg
Hartwig
H
D018171:Agrin / Q000378:metabolism; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism; D016764:Cell Polarity; D049030:Dystroglycans / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission
D018171:Agrin; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D049030:Dystroglycans