Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress.
Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress.
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褪黑素通过减轻内质网应激来减轻红藻氨酸诱导的神经元 Tau 过度磷酸化和记忆缺陷
DOI：
10.3389/fnmol.2018.00005
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发表时间：
2018
影响因子：
4.8
通讯作者：
Shi A
中科院分区：
文献类型：
--
作者：
Shi C;Zeng J;Li Z;Chen Q;Hang W;Xia L;Wu Y;Chen J;Shi A
海人酸（KA）暴露导致神经元变性，其特征在于阿尔茨海默样tau蛋白过度磷酸化和记忆缺陷。褪黑激素（Melatonin，Mel）是一种保护海马神经元免受KA损伤的药物。然而，根本的机制仍然难以捉摸。在目前的研究中，我们研究了褪黑激素对KA诱导的tau蛋白过度磷酸化的保护作用，重点是内质网（ER）应激介导的信号通路。通过使用原代海马神经元和小鼠脑，我们表明KA处理特异性诱导ER应激并激活GSK-3β和CDK 5，这两种主要激酶负责tau磷酸化。ER应激的抑制有效地灭活了GSK-3β和CDK 5。从机制上讲，我们发现KA诱导的ER应激显著激活钙蛋白酶，一种钙依赖性蛋白酶。ER应激或钙蛋白酶的抑制导致KA诱导的GSK-3β和CDK 5活性以及tau磷酸化的降低。此外，GSK-3β或CDK 5抑制未能有效下调ER应激，表明ER应激在GSK-3β或CDK 5上游起作用。值得注意的是，我们的研究结果表明，褪黑激素通过缓解ER应激来对抗KA诱导的神经元变性和tau蛋白过度磷酸化，进一步突出了褪黑激素在KA诱导的神经元缺陷中的保护作用。
Kainic acid (KA) exposure causes neuronal degeneration featured by Alzheimer-like tau hyperphosphorylation and memory deficits. Melatonin (Mel) is known to protect hippocampal neurons against KA-induced damage. However, the underlying mechanisms remain elusive. In the current study, we investigated the protective effect of melatonin on KA-induced tau hyperphosphorylation by focusing on endoplasmic reticulum (ER) stress-mediated signaling pathways. By using primary hippocampal neurons and mouse brain, we showed that KA treatment specifically induced ER stress and activated GSK-3β and CDK5, two major kinases responsible for tau phosphorylation. Inhibition of ER stress efficiently inactivated GSK-3β and CDK5. Mechanistically, we found that KA-induced ER stress significantly activated calpain, a calcium-dependent protease. Inhibition of ER stress or calpain leads to the reduction in KA-induced GSK-3β and CDK5 activities and tau phosphorylation. Moreover, GSK-3β or CDK5 inhibition failed to downregulate ER stress efficiently, suggesting that ER stress functions upstream of GSK-3β or CDK5. Notably, our results revealed that melatonin acts against KA-induced neuronal degeneration and tau hyperphosphorylation via easing ER stress, further highlighting the protective role of melatonin in the KA-induced neuronal defects.
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影响因子：
7.2
作者：
Liu, Xin-An;Song, Jie;Wang, Jian-Zhi
通讯作者：
Wang, Jian-Zhi
DOI：
10.1080/09523367.2016.1233865
发表时间：
2016-05-01
影响因子：
0.6
作者：
Kim, Hyun-Bae;Johnson, John A.;Ha, Peter
通讯作者：
Ha, Peter
影响因子：
2.1
作者：
Jain, A.;Sharma, D.;Bhatnagar, M.
通讯作者：
Bhatnagar, M.
DOI：
10.3233/jad-2009-1069
发表时间：
2009
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Liang Z;Liu F;Iqbal K;Grundke-Iqbal I;Gong CX
通讯作者：
Gong CX
影响因子：
7.2
作者：
Garcia de la Cadena, Selene;Hernandez-Fonseca, Karla;Massieu, Lourdes
通讯作者：
Massieu, Lourdes