The coupling of neural activity and increased blood flow (neurovascular coupling) is vital to brain function. Failure of this coupling occurs early in Alzheimer’s disease (AD) and ‘pure’ tauopathies and induces chronic brain injury, contributing to neurodegeneration. Among other mediators, neurovascular coupling is regulated by nitric oxide (NO) bioavailability. NO formed by the neuronal form of nitric oxide synthase (nNOS) is central to neurovascular coupling, and its production by nNOS-expressing interneurons depends on microtubule- dependent transport of nNOS to dendrites. Tau protein, causally implicated in AD, stabilizes microtubules. Under pathologic conditions, hyperphosphorylated tau detaches from microtubules, destabilizing the microtubule cytoskeleton. Soluble hyperphosphorylated tau aggregates transfer trans-neuronally, promoting native tau phosphorylation and microtubule destabilization in target cells. Among the neuron types targeted by tau pathology in AD are vasculature-associated nNOS-expressing neurons. The functional impact of pathogenic tau on nNOS neurons, and its contribution to brain vascular dysfunction in AD, have not been explored and are not understood. The objective of this proposal is to define mechanisms of pathogenic tau-induced brain vascular dysfunction and determine whether removing pathogenic tau with immunotherapy is a potential treatment for AD. We hypothesize that soluble tau aggregates critically contribute to brain vascular dysfunction in AD by blocking nNOS activation, and that removal of soluble tau aggregates with immunotherapy will prevent and potentially treat brain vascular dysfunction by restoring nNOS activity. Our studies show that aggregation-prone human tau causes neurovascular coupling deficits driven by reduced nNOS activation in models of AD tauopathy;; and that transmission of soluble aggregated tau into neurons blocks nNOS activation, suggesting that pathogenic tau drives brain dysfunction by impairing nNOS. We will test our central hypothesis by pursuing two Specific Aims. In Aim 1, we will define the mechanisms by which soluble tau aggregates impede nNOS activation using in vitro approaches, and identify molecular alterations triggered by tau aggregates in vivo in microvasculature-associated neurons during disease progression in a mouse model of AD tauopathy. In Aim 2, we will establish the therapeutic potential of soluble aggregated tau removal in AD cerebrovascular dysfunction, using antibody-based removal of soluble tau aggregates early in AD progression and after disease onset, and determine, in human AD brains, how accumulation of tau aggregates and molecular alterations identified in Aim 1 correlate with...