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.

中文翻译：

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他克林通过破坏培养的神经元细胞中寡聚乙酰胆碱酯酶的正确组装来诱导内质网应激细胞凋亡

乙酰胆碱酯酶抑制剂 (AChEIs) 是阿尔茨海默病 (AD) 最发达的治疗策略，至少在未来几十年内将用于临床。它们的副作用因药物而异，其机制尚待完全确定。他克林（Cognex）在市场上的退出使其成为一个有趣的案例研究。在这里，我们发现他克林可以破坏内质网 (ER) 中富含脯氨酸的膜锚连接四聚乙酰胆碱酯酶 (AChE) 的正常运输。他克林在表达 AChE 的细胞（例如神经元）中的暴露导致错误折叠的 AChE 在 ER 中的积累。这种错误折叠的酶不能转运到高尔基体/质膜，随后诱导内质网应激及其未折叠蛋白反应的下游信号级联反应。一旦压力过大，ER与线粒体的合作会增加线粒体膜电位的损失。最终，暴露于他克林的细胞失去稳态并经历细胞凋亡。他克林诱导的内质网应激和细胞凋亡与 AChE 的量成正比。其他 AChEI（利凡斯的明、双 (3)-cognitin、daurisoline 和 dauricine）可能通过在神经元细胞中诱导 ER 应激而引起与他克林相同的问题。该结果为用于AD治疗的AChEIs的药物设计和发现提供指导。bis(3)-cognitin、daurisoline 和 dauricine) 可通过在神经元细胞中诱导 ER 应激而引起与他克林相同的问题。该结果为用于AD治疗的AChEIs的药物设计和发现提供指导。bis(3)-cognitin、daurisoline 和 dauricine) 可通过在神经元细胞中诱导 ER 应激而引起与他克林相同的问题。该结果为用于AD治疗的AChEIs的药物设计和发现提供指导。