NITRIC OXIDE SYNTHASE DYSFUNCTION UNDERLIES CEREBROVASCULAR DEFICITS IN MOUSE MODELS OF TAUOPATHY

Abstract

Our laboratory recently reported the accumulation of pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer's disease (AD). The functional consequences of cerebrovascular tau accumulation, however, are not yet understood. The aim of the present study was to determine whether brain microvascular tau accumulation leads to microvascular dysfunction. To this end, we assessed the coupling between increased neural activity and increased cerebral blood flow, a highly regulated processes called neurovascular coupling (NVC), in several different models of tauopathy. Laser Doppler flowmetry was used to determine changes in cerebral blood flow evoked by whisker stimulation, a measure of NVC, in JNPL3, PS19, and hTau mice expressing the P301L mutation, P301S mutation, and wild-type human tau respectively, compared to appropriate controls for each strain. Inhibitors of nitric oxide synthases (NOS) were topically applied on the stimulated barrel cortex during NVC to elucidate the contribution of neuronal NOS (nNOS) and other NOS (endothelial NOS, eNOS) to NVC in each strain. In a separate group of animals, we measured vascular reactivity as endothelium-dependent vasodilation following topical application of acetylcholine (ACh). To assess the impact of pathogenic tau on NOS function, we treated primary neurons or brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS as relative phosphorylated and total enzyme levels in neurons and endothelial cells respectively. Our data indicate that isolated overexpression of WT or mutant tau in models of tauopathy impairs NVC responses, and that this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies show that tauopathy also impairs endothelium-dependent vasoreactivity. We found that soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Thus, pathogenic tau aggregates may impair NOS activation, leading to microvascular dysfunction in tauopathies. Tauopathies are associated with cerebrovascular dysfunction. The inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie microvascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer's disease and potentially other tauopathies.