Rivera-Krstulović Catalina, Duran-Aniotz Claudia
Instituto de Neurociencia Biomédica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Rev Med Chil. 2020 Feb;148(2):216-223. doi: 10.4067/s0034-98872020000200216.
The clinical features of Alzheimer's disease (AD), for example the progressive memory loss, are produced by neuronal loss and synaptic dysfunction. These events have been associated with histopathological alterations in AD brain, including the presence of amyloid plaques and neurofibrillary tangles. Recent studies suggest that cellular stress produced by the aggregation of misfolded proteins leads to alterations in protein homeostasis, that is regulated for the most part by endoplasmic reticulum (ER). The ER is the main compartment involved in the folding and secretion of proteins and is drastically affected in AD neurons. Recent evidence implicates the participation of adaptive responses to stress within the ER in the disease process through a signaling pathway known as the Unfolded Protein Response (UPR) which alleviates the protein aggregation and ER stress. Based on the involvement of ER stress in several diseases, efforts are being done to identify small molecules that can inhibit or activate selective UPR components. Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.
阿尔茨海默病（AD）的临床特征，如进行性记忆丧失，是由神经元丧失和突触功能障碍引起的。这些事件与AD大脑中的组织病理学改变有关，包括淀粉样斑块和神经原纤维缠结的存在。最近的研究表明，错误折叠蛋白聚集产生的细胞应激会导致蛋白质稳态的改变，而蛋白质稳态在很大程度上是由内质网（ER）调节的。内质网是参与蛋白质折叠和分泌的主要细胞器，在AD神经元中受到严重影响。最近的证据表明，内质网内对应激的适应性反应通过一种称为未折叠蛋白反应（UPR）的信号通路参与疾病过程，该通路可减轻蛋白质聚集和内质网应激。基于内质网应激在多种疾病中的作用，人们正在努力寻找能够抑制或激活选择性UPR成分的小分子。在此，我们综述了表明内质网应激在AD病因学中具有功能作用的研究结果。并讨论了在AD背景下减轻内质网应激的可能治疗策略。
