The CNS is sequestered from systemic circulation by a series of barriers that tightly regulate the CNS microenvironment to allow proper functioning of the neural tissue, and provide protection from toxins, pathogens and other potentially harmful agents. One of these barriers, the BBB is formed by specialized endothelial cells (ECs) that have impermeable tight junctions (TJs) and reduced transcellular transcytosis and pinocytosis to restrict the entry of leukocytes, antibodies and other serum proteins into the CNS parenchyma. In the healthy BBB, TJ proteins are degraded and recycled at a low rate via Rab5/Rab7-mediated endolysosomal trafficking and degradation. BBB function is impaired in neuroinflammation which allows paracellular or transcellular migration of leukocytes via either disrupted TJs or increased transcytosis, respectively. However, the mechanisms by which TJ disruption occurs at the BBB in the context of MS/EAE remain poorly understood. Changes in the normal rate of endolysomal trafficking and degradation of TJ proteins may underlie BBB breakdown in EAE/MS. Wnt/B-catenin signaling has been shown to be required for both the development and maintenance of the BBB. Our laboratory has previously shown that spinal cord ECs upregulate the Wnt/B-catenin signaling pathway during EAE, and inhibition of this pathway exacerbates the clinical course of the disease. However, the role of the Wnt/B-catenin signaling pathway in barrier repair during EAE remains unresolved. My thesis project involves investigating whether inhibition of endolysomal degradation and upregulation of Wnt/B-catenin signaling in the neurovasculature prevents BBB breakdown, reduces immune cell infiltration and ameliorates disease outcomes during EAE.