Lee Seung-Eun, Choi Hanul, Shin Nari, Kong Dasom, Kim Nam Gyo, Kim Hee-Yeong, Kim Min-Ji, Choi Soon Won, Kim Young Bong, Kang Kyung-Sun
Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Biomedical Science and Engineering, Konkuk University, Seoul, 05029, Republic of Korea.
Cell Death Discov. 2022 Apr 2;8(1):153. doi: 10.1038/s41420-022-00958-x.
Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases characterized by β-amyloid (Aβ) production and Phosphorylated-Tau (p-Tau) protein in the cerebral cortex. The precise mechanisms of the cause, responsible for disease pathology and progression, are not well understood because there are multiple risk factors associated with the disease. Viral infection is one of the risk factors for AD, and we demonstrated that Zika virus (ZIKV) infection in brain organoids could trigger AD pathological features, including Aβ and p-Tau expression. AD-related phenotypes in brain organoids were upregulated via endoplasmic reticulum (ER) stress and unfolded protein response (UPR) after ZIKV infection in brain organoids. Under persistent ER stress, activated-double stranded RNA-dependent protein kinase-like ER-resident (PERK) triggered the phosphorylation of Eukaryotic initiation factor 2 (eIF2α) and then BACE, and GSK3α/β related to AD. Furthermore, we demonstrated that pharmacological inhibitors of PERK attenuated Aβ and p-Tau in brain organoids after ZIKV infection.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是大脑皮层中存在β-淀粉样蛋白（Aβ）生成和磷酸化tau蛋白（p-Tau）。由于该疾病存在多种风险因素，导致其病因、疾病病理和进展的确切机制尚未完全明确。病毒感染是AD的风险因素之一，我们已证明寨卡病毒（ZIKV）感染脑类器官可引发AD病理特征，包括Aβ和p-Tau的表达。在脑类器官中感染ZIKV后，通过内质网（ER）应激和未折叠蛋白反应（UPR），脑类器官中与AD相关的表型上调。在持续的内质网应激下，活化的双链RNA依赖性蛋白激酶样内质网驻留蛋白（PERK）触发真核起始因子2（eIF2α）的磷酸化，进而导致与AD相关的β-分泌酶（BACE）以及糖原合成酶激酶3α/β（GSK3α/β）的磷酸化。此外，我们还证明PERK的药理学抑制剂可减轻ZIKV感染后脑类器官中Aβ和p-Tau的生成。
