Targeting cerebrovascular Wnt/beta-catenin signaling to reverse brain endothelial damage induced by SARS-CoV-2 infection

Abstract Many COVID-19 survivors experience long-lasting neurological post-acute sequelae of COVID-19 (NeuroPASC) including cognitive, cerebrovascular, and neurological disorders. The causes of NeuroPASC are not understood. However, evidence suggests that blood-brain barrier damage may contribute to NeuroPASC. Identifying mechanisms that regulate the brain endothelial cell response in NeuroPASC is therefore important. Wnt/β-catenin signaling plays a critical role in maintaining integrity of the blood-brain barrier. This grant will test the novel mechanism that Wnt/β-catenin dysregulation in brain endothelial cells contributes to NeuroPASC by increasing blood-brain barrier permeability and neuroinflammation. We will determine the effect of age on brain endothelial cell signaling and blood-brain barrier permeability for the resolution of NeuroPASC. We will define the mechanism by which Wnt/β-catenin activation reverses blood-brain barrier leakage and memory impairment in NeuroPASC. We will determine the extent through which transcellular blood-brain barrier permeability contributes to NeuroPASC. These studies could identify future therapeutic strategies leveraging Wnt/β-catenin signaling to improve chronic post-infectious neurological diseases.