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- W3048203223 abstract "Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer’s disease and frontotemporal dementia, diseases characterized by the accumulation of hyperphosphorylated forms of the microtubule-associated protein tau. However, it is unclear whether tau contributes to these neurovascular alterations independent of neurodegeneration. We report that mice expressing mutated tau exhibit a selective suppression of neural activity-induced cerebral blood flow increases that precedes tau pathology and cognitive impairment. This dysfunction is attributable to a reduced vasodilatation of intracerebral arterioles and is reversible by reducing tau production. Mechanistically, the failure of neurovascular coupling involves a tau-induced dissociation of neuronal nitric oxide synthase (nNOS) from postsynaptic density 95 (PSD95) and a reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. These data identify glutamatergic signaling dysfunction and nitric oxide deficiency as yet-undescribed early manifestations of tau pathobiology, independent of neurodegeneration, and provide a mechanism for the neurovascular alterations observed in the preclinical stages of tauopathies. Park et al. demonstrate in tauopathy models that tau disrupts the interaction between neuronal nitric oxide synthase and PSD95, uncoupling glutamatergic synaptic activity from nitric oxide production and dampening the hemodynamic response to activation." @default.
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- W3048203223 date "2020-08-10" @default.
- W3048203223 modified "2023-10-17" @default.
- W3048203223 title "Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration" @default.
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- W3048203223 doi "https://doi.org/10.1038/s41593-020-0686-7" @default.
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