Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression
Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression
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Tau 积累通过抑制 NMDA 受体表达触发 STAT1α 依赖性记忆缺陷
DOI：
10.15252/embr.201847202
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发表时间：
2019-06-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Jian-Zhi
中科院分区：
文献类型：
--
作者：
Li, Xiao-Guang;Hong, Xiao-Yue;Wang, Jian-Zhi
细胞内tau积聚形成神经原纤维缠结是阿尔茨海默病（AD）的标志性病理，但tau积聚如何诱导突触损伤尚不清楚。通过过表达人类全长野生型tau（称为hTau）来模拟散发性AD患者大脑中的tau异常，我们发现hTau积累激活JAK2在Tyr701位点磷酸化STAT1（信号换能器和转录激活因子1），导致STAT1二聚化、核易位及其激活。STAT1激活通过直接结合GluN1、GluN2A和GluN2B启动子的特异性GAS元件抑制n -甲基- d -天冬氨酸受体（NMDARs）的表达，而在STAT1（flox/flox）小鼠中，通过AAV-Cre敲低STAT1或表达显性阴性Y701F-STAT1有效地恢复htaau诱导的NMDAR表达抑制，改善突触功能和记忆性能。这些研究结果表明，hTau积累通过JAK2/ stat1诱导的NMDAR表达抑制而损害突触可塑性，揭示了hTau相关突触和记忆缺陷的新机制。
Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1(flox/flox) mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.