Askari Sahar, Javadpour Pegah, Rashidi Fatemeh Sadat, Dargahi Leila, Kashfi Khosrow, Ghasemi Rasoul
Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 11151-19857, Iran.
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran 11151-19857, Iran.
Life (Basel). 2022 Sep 2;12(9):1374. doi: 10.3390/life12091374.
Accumulation of misfolded proteins, known as endoplasmic reticulum (ER) stress, is known to participate in Alzheimer's disease (AD). AD is also correlated with impaired central insulin signaling. However, few studies have probed the relationship between memory, central ER stress, inflammation, hippocampal mitogen-activated protein kinase (MAPK) activity and insulin resistance. The present study aimed to investigate the causative role and underlying mechanisms of brain ER stress in memory impairment and develop a reliable animal model for ER-mediated memory loss. Thapsigargin (TG), a known ER stress activator, was centrally administered. The cognitive function of animals was evaluated by the Morris Water Maze (MWM). To verify the induction of central ER stress, we investigated the mRNA expression of UPR markers in the hippocampus. In addition, the activation of ER stress markers, including Bip, CHOP, and some related apoptosis and pro-inflammatory proteins, such as caspase-3, Bax, Bcl-2, TNF-α, MAPK, and insulin signaling markers, were assessed by Western-blots. The results demonstrated that TG impairs spatial cognition and hippocampal insulin signaling. Meanwhile, molecular results showed a concurrent increment of hippocampal UPR markers, apoptosis, P38 activity, and TNF-α. This study introduced TG-induced ER stress as a pharmacological model for memory impairment in rats and revealed some underlying mechanisms.
错误折叠蛋白的积累，即内质网（ER）应激，已知参与阿尔茨海默病（AD）。AD还与中枢胰岛素信号受损有关。然而，很少有研究探究记忆、中枢ER应激、炎症、海马丝裂原活化蛋白激酶（MAPK）活性和胰岛素抵抗之间的关系。本研究旨在探讨脑ER应激在记忆障碍中的致病作用及潜在机制，并建立一种可靠的ER介导记忆丧失的动物模型。已知的ER应激激活剂毒胡萝卜素（TG）经中枢给药。通过莫里斯水迷宫（MWM）评估动物的认知功能。为了验证中枢ER应激的诱导，我们研究了海马中未折叠蛋白反应（UPR）标志物的mRNA表达。此外，通过蛋白质免疫印迹法评估ER应激标志物的激活情况，包括结合免疫球蛋白蛋白（Bip）、C/EBP同源蛋白（CHOP），以及一些相关的凋亡和促炎蛋白，如半胱天冬酶-3（caspase-3）、促凋亡蛋白Bax、抗凋亡蛋白Bcl-2、肿瘤坏死因子-α（TNF-α）、MAPK，以及胰岛素信号标志物。结果表明，TG损害空间认知和海马胰岛素信号。同时，分子结果显示海马UPR标志物、细胞凋亡、P38活性和TNF-α同时增加。本研究引入了TG诱导的ER应激作为大鼠记忆障碍的药理学模型，并揭示了一些潜在机制。
