Liu_2021_Mol.Pharmacol__

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 whose mechanism remain to be fully established. The withdrawal of tacrine (Cognex(a)) 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 AChE in the endoplasmic reticulum (ER). The exposure of tacrine in cells expressing AChE, e.g. neuron, caused an accumulation of the misfolded AChE in the ER. This misfolded enzyme was not able to transport to Golgi/plasma membrane, which subsequently induced ER stress and its downstream signaling cascade of unfolded protein response (UPR). 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 undergone 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 AChEIs are the most developed treatment strategies for Alzheimer's disease (AD) and will be used in clinic for at least the next decades. Our study reports tacrine and other AChEIs disrupt the proper trafficking of AChE 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.