Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.
Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.
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DOI：
10.1038/s41593-020-0686-7
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发表时间：
2020-09
影响因子：
25
通讯作者：
Iadecola C
中科院分区：
文献类型：
--
作者：
Park L;Hochrainer K;Hattori Y;Ahn SJ;Anfray A;Wang G;Uekawa K;Seo J;Palfini V;Blanco I;Acosta D;Eliezer D;Zhou P;Anrather J;Iadecola C
脑血管异常已经作为阿尔茨海默病和额颞叶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的过度磷酸化形式的积累。然而，目前尚不清楚tau蛋白是否独立于神经退行性变而导致这些神经血管改变。我们报告说，表达突变的tau蛋白的小鼠表现出选择性抑制神经活动诱导的脑血流量增加，在tau蛋白病理和认知障碍之前。这种功能障碍可归因于脑内小动脉的血管舒张减少，并且通过降低tau蛋白的产生而可逆。从机制上讲，神经血管偶联的失败涉及tau诱导的神经元一氧化氮合酶从突触后-密度-95的解离，以及在神经元能突触活动期间有效的血管扩张剂一氧化氮的产生减少。这些数据将神经元能信号传导功能障碍和一氧化氮缺乏确定为尚未描述的独立于神经变性的tau病理生物学的早期表现，并提供了在tau蛋白病的临床前阶段观察到的神经血管改变的机制。
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.
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影响因子：
4.3
作者：
Brøchner CB;Holst CB;Møllgård K
通讯作者：
Møllgård K
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
DOI：
10.1523/jneurosci.3367-10.2010
发表时间：
2010-09-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Coleman CG;Wang G;Park L;Anrather J;Delagrammatikas GJ;Chan J;Zhou J;Iadecola C;Pickel VM
通讯作者：
Pickel VM
影响因子：
4.8
作者：
Christopherson, KS;Hillier, BJ;Bredt, DS
通讯作者：
Bredt, DS
影响因子：
4.2
作者：
Dopper, Elise G. P.;Chalos, Vicky;van Swieten, John C.
通讯作者：
van Swieten, John C.