Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice
Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice
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美金刚差异调节小鼠不同持续时间的慢性束缚应激诱导的 tau 磷酸化
DOI：
10.1155/2019/4168472
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发表时间：
2019-01-01
影响因子：
3.1
通讯作者：
Zhu, Cuiqing
中科院分区：
文献类型：
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作者：
Liu, Yunsheng;Cao, Lan;Zhu, Cuiqing
暴露于慢性精神压力与阿尔茨海默病相关的tau过度磷酸化和谷氨酸神经传递异常有关。然而，慢性精神应激下大脑皮层谷氨酸能功能障碍与tau蛋白磷酸化之间的病理关系尚不完全清楚。本研究研究了非竞争性n -甲基- d -天冬氨酸（NMDA）受体拮抗剂美金刚（MEM， 5和10 mg/kg）对小鼠慢性抑制应激（CRS-）诱导的tau磷酸化的影响。连续给予CRS 16或28天（每天1小时）可诱导大脑中显著的tau磷酸化。MEM处理以剂量依赖的方式抑制16天CRS诱导的磷酸化tau （P-tau）水平升高。P-tau的减少伴随着CRS诱导的GSK3β和CDK5表达上调和PP2A活性下调的减弱。此外，MEM降低了crs诱导的额叶皮层NMDA受体亚基（GluN2A, GluN2B）水平的上调。然而，在CRS治疗28天后，MEM显著增强了额叶皮层和其他大脑皮层区域的tau磷酸化。MEM对crs诱导的tau磷酸化的刺激作用与AKT、JNK和GSK3β活性升高，PP2A失活，Pin1和HSP70下调相关。此外，MEM不能有效逆转28天CRS诱导的NMDA受体上调，甚至会增加GluN2B亚基水平。与MEM对P-tau水平的持续依赖性作用相反，MEM在两种方案中都产生抗焦虑作用，这是由升高的迷宫测试显示的。然而，MEM不影响CRS诱导的体重减轻。因此，MEM对crs诱导的tau磷酸化有明显的影响，这可能与GluN2B的表达有关。MEM对P-tau水平的不同影响对其临床应用具有重要意义。
Exposure to chronic psychiatric stress has been linked to Alzheimer's disease-related tau hyperphosphorylation and abnormalities in glutamate neurotransmission. However, the pathological relationship between glutamatergic dysfunction and tau phosphorylation in the cerebral cortex under chronic psychiatric stress is not fully understood. The present study investigated the effects of memantine (MEM, 5 and 10 mg/kg), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on chronic restraint stress- (CRS-) induced tau phosphorylation in mice. CRS administered for 16 or 28 consecutive days (1 h daily) induced significant tau phosphorylation in the brain. MEM treatment suppressed the elevation of phosphorylated tau (P-tau) levels induced by 16-day CRS in a dose-dependent manner. P-tau reduction was accompanied by the attenuation of the upregulation of GSK3β and CDK5 expression and the downregulation of PP2A activity induced by CRS. Additionally, MEM reduced CRS-induced upregulation of NMDA receptor subunit levels (GluN2A, GluN2B) in the frontal cortex. However, MEM markedly enhanced tau phosphorylation in the frontal cortex and other cerebral cortical regions following 28 days of CRS. The stimulatory effect of MEM on CRS-induced tau phosphorylation was correlated with increased activities of AKT, JNK, and GSK3β, inactivation of PP2A, and downregulation of Pin1 and HSP70. Moreover, MEM did not effectively reverse the NMDA receptor upregulation induced by 28-day CRS and even increased GluN2B subunit levels. In contrast to the duration-dependent effects of MEM on P-tau levels, MEM produced an anxiolytic effect in both regimens as revealed by elevated plus maze testing. However, MEM did not affect the body weight reduction induced by CRS. Thus, MEM exerts distinctive effects on CRS-induced tau phosphorylation, which might be related to the expression of GluN2B. The differential effects of MEM on P-tau levels have crucial implications for its clinical application.