Blood-brain barrier alterations in the cerebral cortex in experimental autoimmune encephalomyelitis

Area of Science:

• Neuroimmunology
• Vascular Biology
• Demyelinating Diseases

Background:

• The exact mechanisms driving cerebral cortical lesions in multiple sclerosis (MS) remain unclear.
• Understanding the role of microvasculature in MS pathophysiology is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the changes in cerebral cortex microvessels during immune-mediated demyelination in a mouse model of MS.
• To examine the expression and localization of key endothelial tight junction proteins and associated molecules in the context of experimental autoimmune encephalomyelitis (EAE).

Main Methods:

• Immunolocalization of claudin-5, occludin, caveolin-1, and Glut 1 in the cerebral cortex of EAE-affected mice.
• Assessment of microvascular integrity using fluorescein isothiocyanate-dextran leakage assays.
• Analysis of microglial activation and inflammatory infiltrates.

Main Results:

• EAE mice exhibited subpial and deeper cortical lesions with activated microglia but minimal perivascular inflammation.
• Microvascular endothelial cells showed increased caveolin-1 and loss of claudin-5 and occludin at intercellular junctions.
• Early disease stages revealed claudin-5 clustering and vacuole formation, while occludin became diffusely cytoplasmic in later stages.
• Evidence suggested claudin-5 internalization via autophagy and confirmed blood-brain barrier leakage.

Conclusions:

• Cerebral cortical lesions in MS involve a distinct microvascular pathology characterized by the differential disruption of claudin-5 and occludin.
• This microvascular disease occurs concurrently with demyelination, even with minimal inflammation, highlighting its potential contribution to MS pathogenesis.
• Findings suggest that targeting microvascular integrity may offer a novel therapeutic strategy for MS.