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Endothelial Wnt/β-catenin modulates blood-brain barrier integrity in a mouse model of multiple sclerosis

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Blood-brain barrier (BBB) breakdown is a contributing factor in many neurological diseases, including Multiple Sclerosis (MS). MS is an inflammatory disease in which auto-reactive T-cells become activated towards myelin, infiltrate into the CNS, and mediate myelin and eventually neuronal destruction. The majority of patients have MS manifest as a relapsing-remitting type, in which there is a flare-up of symptoms as CNS inflammatory infiltration and damage occur, followed by the subsiding of symptoms. It is known the BBB is degraded before relapses resulting in symptoms and is subsequently repaired during the remission phase. However, it is still not known what pathways mediate the repair of the BBB in the remission phase. The Wnt/β-catenin pathway controls development of the BBB; however its role in repairing the BBB in diseases where it is impaired remains unclear.

The focus of this research was to investigate whether the Wnt/β-catenin pathway is active during a mouse model of MS and elucidate the role that this pathway might play on endothelial barrier properties and immune cell infiltration in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). I demonstrate that the Wnt/β-catenin pathway is upregulated in CNS endothelial cells during EAE progression and genetic ablation of Wnt/β-catenin activity in endothelial cells exacerbated EAE clinical presentation, immune cell infiltration, demyelination and enhances vascular expression of the adhesion molecule VCAM1 and the transcytosis protein Caveolin-1, without affecting tight junction proteins (Chapter 3). Chemical activation of the Wnt/β-catenin pathway during EAE was unsuccessful and failed to alter EAE clinical disease course (Chapter 4). Lastly, I provide evidence that the Wnt/β-catenin pathway is highly upregulated in ECs within MS lesions, paralleling my findings in the EAE mouse model (Chapter 5). This study opens the possibility to develop a new target for therapeutics that can enhance BBB integrity during MS.

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