Project Summary/Abstract Alzheimer’s disease is a progressive neurodegenerative disorder that causes significant individual suffering and a major public health burden. The poorly elucidated pathophysiology of Alzheimer’s disease limits the development of effective disease modifying therapy and, as a result, there are currently no therapeutic interventions that halt or reverse the disease process. It is becoming clear that cerebrovascular dysfunction and cardiovascular disease are major contributors to neurodegeneration and dementia. Cerebrovascular dysfunction is the first and most significant abnormality that occurs in Alzheimer’s disease and may interact with other pathological factors to drive the pathological progression of Alzheimer’s disease. The two hallmark pathologies of Alzheimer’s disease are the extracellular β-amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Preliminary studies show that transmissible soluble tau aggregates, a species of tau that is implicated in the spread of tau pathology and neurodegeneration, accumulate in cerebrovascular endothelial cells in vitro, in several mouse models of tauopathy, and in human patients diagnosed with Alzheimer’s disease or other tauopathies. Exposure to soluble tau aggregates causes endothelial cell dysfunction in vitro. Furthermore, mouse models of tauopathy show impaired endothelial function by middle age. The mechanism by which soluble tau aggregates are transmitted to endothelial cells and their role in the development of cerebrovascular dysfunction, however, are unclear. Published literature show that soluble tau aggregates spread from neuron to neuron by binding cell surface heparan sulfate proteoglycans (HSPG). Based on these findings, the proposed studies will test the hypothesis that soluble tau aggregate transmission to microvascular endothelial cells is mediated by tau binding to cell surface HSPG and drives endothelial dysfunction in vitro and in vivo. Aim 1 will determine the role of tau binding to cell surface HSPG in soluble tau aggregate entry into endothelial cells and the development of endothelial cell dysfunction in vitro. Aim 2 will determine the role of soluble tau aggregates in the development of endothelial dysfunction in a mouse model of tauopathy by removing soluble tau aggregates from the brain using antibody treatment. These studies will make use of the detailed specificity of in vitro techniques and the translatability of in vivo approaches to characterize a novel element of cerebrovascular pathology and Alzheimer’s disease pathophysiology. Completion of the studies proposed will provide crucial knowledge about the etiological determinants of Alzheimer’s disease. This knowledge can be used in the development of therapeutic interventions that target cerebrovascular dysfunction, the first abnormality that occurs in Alzheimer’s disease. The completion of the studies proposed and the training activities detailed in this application ...