Role of Sox18 in neurovascular dysfunction in Alzheimer's disease - PROJECT SUMMARY Cerebral blood vessels are critical to deliver blood, containing oxygen and nutrients, to every neuron and glial cell in the brain. In addition, the endothelial cells comprising central nervous system blood vessels possess unique properties, termed the blood-brain barrier (BBB), that allow them to tightly regulate the movement of ions, molecules, and cells between the blood and the brain, thus, tightly regulating the extracellular environment of the brain. Studies have indicated that neurovascular dysfunction, including hypoperfusion and BBB dysfunction, may be an important component of Alzheimer’s disease pathogenesis. This vascular dysfunction could lead to accumulation waste products such as amyloid, leakage of serum components to the brain, and increased neuroinflammation, all of which could have important impacts on the neurodegeneration that is observed in patients with Alzheimer’s disease. Despite the potential importance of neurovascular dysfunction, very little is known about the molecular changes to cerebral blood vessels in patients with Alzheimer’s disease, and how these changes may affect neurovascular function and the progression of Alzheimer’s disease pathology. We have performed proteomics on blood vessels isolated from human patients with Alzheimer’s disease and from age and sex matched controls. Interestingly, we found downregulation of pathways involved in angiogenesis and barrier formation, which may account for the hypoperfusion and BBB dysfunction, respectively, observed in Alzheimer’s disease patients. The proteomic data also showed robust downregulation of the transcription factor SOX18 in the blood vessels of patients with Alzheimer’s disease. We further used mice models to downregulate Sox18 expression in brain endothelial cells and found very similar changes to those found in Alzheimer’s disease patients, including a downregulation of angiogenesis and barrier formation pathways. Therefore, we hypothesize that downregulation of SOX18 in brain endothelial cells is key to the neurovascular dysfunction observed in patients with Alzheimer’s disease. In this grant we will first examine the role of Sox18 in modulating neurovascular function in mice, including angiogenesis and barrier formation. We will then use human induced pluripotent stem cell models of the BBB to identify the molecular mechanisms by which SOX18 regulates neurovascular function. We will then determine whether modulating Sox18 expression can alter the disease course in multiple mouse models of Alzheimer’s disease. These experiments will allow us to understand the role of SOX18 in neurovascular function, and determine whether targeting SOX18 could limit the pathogenesis of Alzheimer’s disease.
