title: Blood-brain barrier alterations in the cerebral cortex in experimental autoimmune encephalomyelitis.
abstract: The pathophysiology of cerebral cortical lesions in multiple sclerosis (MS) is not understood. We investigated cerebral cortex microvessels during immune-mediated demyelination in the MS model chronic murine experimental autoimmune encephalomyelitis (EAE) by immunolocalization of the endothelial cell tight junction (TJ) integral proteins claudin-5 and occludin, a structural protein of caveolae, caveolin-1, and the blood-brain barrier-specific endothelial transporter, Glut 1. In EAE-affected mice, there were areas of extensive subpial demyelination and well-demarcated lesions that extended to deeper cortical layers. Activation of microglia and absence of perivascular inflammatory infiltrates were common in these areas. Microvascular endothelial cells showed increased expression of caveolin-1 and a coincident loss of both claudin-5 and occludin normal junctional staining patterns. At a very early disease stage, claudin-5 molecules tended to cluster and form vacuoles that were also Glut 1 positive; the initially preserved occludin pattern became diffusely cytoplasmic at more advanced stages. Possible internalization of claudin-5 on TJ dismantling was suggested by its coexpression with the autophagosomal marker MAP1LC3A. Loss of TJ integrity was confirmed by fluorescein isothiocyanate-dextran experiments that showed leakage of the tracer into the perivascular neuropil. These observations indicate that, in the cerebral cortex of EAE-affected mice, there is a microvascular disease that differentially targets claudin-5 and occludin during ongoing demyelination despite only minimal inflammation.
authors.affiliation: Department of Basic Medical Sciences, Human Anatomy and Histology Unit, University of Bari School of Medicine, Bari, Italy. m.errede@histology.uniba.it
authors.forename: Mariella
authors.initials: M
authors.lastname: Errede
authors.forename: Francesco
authors.initials: F
authors.lastname: Girolamo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrara
authors.forename: Maurizio
authors.initials: M
authors.lastname: Strippoli
authors.forename: Sara
authors.initials: S
authors.lastname: Morando
authors.forename: Valentina
authors.initials: V
authors.lastname: Boldrin
authors.forename: Marco
authors.initials: M
authors.lastname: Rizzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Perris
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Luisa
authors.initials: L
authors.lastname: Roncali
authors.forename: Daniela
authors.initials: D
authors.lastname: Virgintino
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051242:Caveolin 1 / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D062507:Claudin-5 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin / Q000378:metabolism
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D051272:Glucose Transporter Type 1; D062793:Occludin; C568986:Ocln protein, mouse; C495678:Slc2a1 protein, mouse