Alzheimer's disease (AD) is the leading cause of age-related cognitive impairment for which there are no treatments. The structural and functional integrity of the brain requires a continuous supply of oxygen and glucose through blood flow, well matched to its dynamic and regionally diverse energy needs. Accordingly, neural activity increases blood flow in active brain regions, a phenomenon termed functional hyperemia. Functional hyperemia depends in large part on the link between NMDA receptor activity and neuronal production of the potent vasodilator nitric oxide (NO), and requires tissue plasminogen activator (tPA) for its full expression. Increasing evidence indicates that alterations in the regulation of the cerebral microcirculation play a significant role in the pathogenesis of AD by reducing the cerebral blood supply, but the mechanisms of such neurovascular dysfunction have not been fully elucidated. Most studies have focused on the damaging cerebrovascular effects of Aβ. However, the role of tau, a key pathogenic factor in AD, remains virtually unexplored. There is a strong rationale for investigating tau. For example, in neurodegenerative diseases caused by tau mutations (tauopathies), in which Aβ is not present, there is evidence of cerebrovascular dysfunction early in the disease course, suggesting that tau exerts pathogenic vascular effects independently of Aβ. Furthermore, hyperphosphorylated tau alters NMDA receptor signaling, which is essential for the neuronal NO production driving functional hyperemia. Based on these scientific premises, we will test the central hypothesis that pathological tau alters neurovascular coupling by impairing the ability of NMDA receptors to trigger NO production, an effect occurring prior to neurodegeneration and cognitive deficits. To this end, we will use state-of-the-art multidisciplinary approaches to investigate neurovascular regulation in mouse models of tauopathies, and in vitro approaches to explore the neurophysiological and molecular mechanisms of the effects. We will test the following hypotheses: (a) Tau disrupts neurovascular function prior to the onset of tau pathology and neurodegeneration; (b) The neurovascular dysfunction induced by tau is due to uncoupling of NMDA receptor activity from NO production; (c) NMDA receptor uncoupling from NO production and neurovascular dysfunction result from a deficit in tPA caused by upregulation of the endogenous tPA inhibitor PAI-1. The findings will begin to shed light on the vascular effects of pathological tau, thereby filling a knowledge gap in our understanding of the neurovascular dysfunction of AD and other tauopathies.