Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.

Abstract

Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer’s disease and frontotemporal dementia, diseases characterized by accumulation of hyperphosphorylated forms of the microtubule associated protein tau. However, it is unclear if 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. The dysfunction is attributable to reduced vasodilatation of intracerebral arterioles and is reversible by turning down tau production. Mechanistically, the failure of neurovascular coupling involves tau-induced dissociation of neuronal nitric oxide synthase from post synaptic-density-95 and reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. The 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.