Energy substrates must be delivered to the brain continuously through its blood supply. Failure of this process has devastating consequences because brain function depends on the timely delivery of energy substrates to neurons through blood flow. Accumulating evidence suggests that Alzheimer’s disease (AD) is a multifactorial heterogeneous disease driven by multiple pathophysiological contributors, including brain vascular dysfunction. Consistent with this, decreased cerebral blood flow is an early biomarker of AD. There is an urgent need to understand brain vascular mechanisms of AD since they may constitute the most therapeutically addressable biological pathway underlying dementia. Tau protein, causally implicated in AD, stabilizes microtubules. In AD, tau misfolds, destabilizing the microtubule cytoskeleton, and is then transferred trans-neuronally, promoting tau aggregation and microtubule destabilization in target cells. We found, for the first time, that pathogenic tau is also transmitted to brain microvascular endothelial cells, where it destabilizes microtubules, diminishes activity of the endothelial form of nitric oxide synthase, induces endothelial cell senescence, and causes profound brain vascular dysfunction in models of tauopathy. The mechanisms by which pathogenic tau induces brain microvascular endothelial cell (BMEC) dysfunction and senescence, and the role of tau-induced BMEC dysfunction and senescence in the etiology of AD have not been explored before. Our goal is to define the mechanisms of pathogenic tau-induced brain vascular dysfunction and their involvement in AD, and determine whether (a) removal of pathogenic tau or (b) removal of senescent brain microvascular endothelial cells could be used to delay (or potentially treat) AD. Our hypothesis is that pathogenic tau transmission to BMEC drives brain vascular dysfunction in AD by impairing BMEC function and by promoting BMEC senescence. We will test our hypothesis with studies that will (Aim 1) identify tau-induced molecular alterations that result in brain endothelial cell dysfunction and senescence; and (Aim 2) establish the therapeutic potential of (a) pathogenic tau or (b) senescent brain microvascular endothelial cell removal in AD, and determine, in human brain, how microvascular tau and molecular alterations identified in Aim 1 are linked to AD progression. Our work will address an entirely new aspect of AD pathophysiology, the accumulation of tau in brain microvasculature and its transmission to brain endothelial cells, that induces endothelial cell dysfunction and senescence, and will define whether pathogenic tau and the cellular events it triggers can be targeted therapeutically. These studies are significant, because once we know how pathogenic tau impairs brain vascular function we will be able to manipulate those mechanisms in AD and other tauopathies. Our studies will pioneer research on a new cellular target of tau toxicity -brain vascular endothelial cel...