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.

脑血管异常已经作为阿尔茨海默氏病和额颞痴呆的临床前表现出现，这些疾病的特征在于微管相关蛋白tau的高磷酸化形式的积累。但是，尚不清楚tau是否与神经退行性变无关地促成这些神经血管改变。我们报告说，表达突变的tau的小鼠表现出选择性的抑制神经活动引起的脑血流量的增加，其先于tau病理和认知障碍。这种功能障碍可归因于脑小动脉血管舒张减少，并且可通过减少tau产生而逆转。机械上，神经血管偶联的失败涉及tau诱导的神经元一氧化氮合酶（nNOS）与突触后密度95（PSD95）的解离，以及在谷氨酸能突触活动过程中有效的血管扩张剂一氧化氮的产生减少。这些数据确定谷氨酸能信号功能障碍和一氧化氮缺乏是尚未描述的tau病理生物学的早期表现，独立于神经退行性病变，并为在Tauopathies的临床前阶段观察到的神经血管改变提供了一种机制。