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: Mariella Errede, Francesco Girolamo, Giovanni Ferrara, Maurizio Strippoli, Sara Morando, Valentina Boldrin, Marco Rizzi, Antonio Uccelli, Roberto Perris, Caterina Bendotti, Mario Salmona, Luisa Roncali, Daniela Virgintino
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 71 Issue 10 Pg. 840-54 (Oct 2012) ISSN: 1554-6578 [Electronic] England
• PMID: 23001217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cav1 protein, mouse
• Caveolin 1
• Claudin-5
• Cldn5 protein, mouse
• Glucose Transporter Type 1
• Occludin
• Ocln protein, mouse
• Slc2a1 protein, mouse

Topics

• Animals
• Blood-Brain Barrier (metabolism, pathology, physiopathology)
• Caveolin 1 (metabolism)
• Cerebral Cortex (metabolism, pathology, physiopathology)
• Claudin-5 (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (metabolism, pathology, physiopathology)
• Female
• Glucose Transporter Type 1 (biosynthesis, metabolism)
• Mice
• Mice, Inbred C57BL
• Occludin (metabolism)