Tacrine Induces Endoplasmic Reticulum–Stressed Apoptosis via Disrupting the Proper Assembly of Oligomeric Acetylcholinesterase in Cultured Neuronal Cells
Tacrine Induces Endoplasmic Reticulum–Stressed Apoptosis via Disrupting the Proper Assembly of Oligomeric Acetylcholinesterase in Cultured Neuronal Cells
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DOI：
10.1124/molpharm.121.000269
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发表时间：
2021-09
影响因子：
3.6
通讯作者：
Etta Y L Liu;Shinghung Mak;Xiangpeng Kong;Yingjie Xia;K. Kwan;M. L. Xu;Karl W. K. Tsim
中科院分区：
文献类型：
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作者：
Etta Y L Liu;Shinghung Mak;Xiangpeng Kong;Yingjie Xia;K. Kwan;M. L. Xu;Karl W. K. Tsim
乙酰胆碱酯酶抑制剂(AChEIs)是阿尔茨海默病(AD)最成熟的治疗策略，至少在未来几十年内将用于临床。它们的副作用在不同的药物之间有很大的差异，机制还有待完全确定。他克林(康耐视)退出市场使其成为一个有趣的案例。在这里，我们发现他克林可以破坏富含脯氨酸的膜锚定连接的四聚乙酰胆碱酯酶(AChE)在内质网(ER)的正常运输。他克林暴露在表达AChE的细胞中，例如神经元，导致错误折叠的AChE在内质网中积聚。这种错误折叠的酶不能运输到高尔基体/质膜上，从而引发内质网胁迫及其下游未折叠蛋白反应的信号级联反应。一旦压力过大，内质网与线粒体的协同作用增加了线粒体膜电位的损失。最终，暴露于他克林的细胞失去了动态平衡，发生了凋亡。他克林诱导的内质网应激和细胞凋亡与AchE的含量成正比。其他AChEIs(利凡斯明、双(3)-知母素、蝙蝠葛素和蝙蝠葛碱)可通过在神经细胞中诱导内质网应激而引起与他克林相同的问题。这些结果为设计和发现治疗AD的AChEIs提供了指导。意义陈述乙酰胆碱酯酶抑制剂(AChEIs)是阿尔茨海默病(AD)最成熟的治疗策略，至少在未来几十年内将用于临床。这项研究报告，他克林和其他AChEIs扰乱了内质网中乙酰胆碱酯酶的正常运输。最终，诱导神经元和其他细胞的凋亡。这些结果为设计和发现治疗AD的AChEIs提供了指导。
Acetylcholinesterase inhibitors (AChEIs), the most developed treatment strategies for Alzheimer’s disease (AD), will be used in clinic for, at least, the next decades. Their side effects are in highly variable from drug to drug with mechanisms remaining to be fully established. The withdrawal of tacrine (Cognex) in the market makes it as an interesting case study. Here, we found tacrine could disrupt the proper trafficking of proline-rich membrane anchor-linked tetrameric acetylcholinesterase (AChE) in the endoplasmic reticulum (ER). The exposure of tacrine in cells expressing AChE, e.g., neurons, caused an accumulation of the misfolded AChE in the ER. This misfolded enzyme was not able to transport to the Golgi/plasma membrane, which subsequently induced ER stress and its downstream signaling cascade of unfolded protein response. Once the stress was overwhelming, the cooperation of ER with mitochondria increased the loss of mitochondrial membrane potential. Eventually, the tacrine-exposed cells lost homeostasis and underwent apoptosis. The ER stress and apoptosis, induced by tacrine, were proportional to the amount of AChE. Other AChEIs (rivastigmine, bis(3)-cognitin, daurisoline, and dauricine) could cause the same problem as tacrine by inducing ER stress in neuronal cells. The results provide guidance for the drug design and discovery of AChEIs for AD treatment. SIGNIFICANCE STATEMENT Acetylcholinesterase inhibitors (AChEIs) are the most developed treatment strategies for Alzheimer’s disease (AD) and will be used in clinic for at least the next decades. This study reports that tacrine and other AChEIs disrupt the proper trafficking of acetylcholinesterase in the endoplasmic reticulum. Eventually, the apoptosis of neurons and other cells are induced. The results provide guidance for drug design and discovery of AChEIs for AD treatment.