Wu Yue, Chen Qingjie, Wen Bing, Wu Ninghua, He Benhong, Chen Juan
Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China.
Front Pharmacol. 2021 Jul 19;12:640758. doi: 10.3389/fphar.2021.640758. eCollection 2021.
Alzheimer's disease (AD) is tightly related to endoplasmic reticulum stress (ER stress), which aggravates two dominant pathological manifestations of AD: senile plaques and neurofibrillary tangles. Berberine is widely applied in the clinical treatment of many diseases and is reported to have anti-AD effects. In the present study, berberine was shown to ameliorate ER stress and cognitive impairment in APP/PS1 mice. We found ER stress plays a role as a central hub for signal transduction, which was evidenced by the hyperactivation of glycogen synthase kinase 3β (GSK3β) to phosphorylate tau and the activation of PRKR-like endoplasmic reticulum kinase (PERK) subsequently to phosphorylate eukaryotic translation initiation factor-2 α (eIF2α). Also, eIF2α has regulated the expression of beta-site APP cleaving enzyme-1 (BACE1), which cleaves APP into pro-oligomerized amyloid beta 42 (Aβ), the main component of senile plaques, proven by using siRNA targeting at eIF2α. Mechanically, berberine can reduce GSK3β activity, contributing to the downregulation of tau phosphorylation. Berberine also suppressed Aβ production inhibiting the PERK/eIF2α/BACE1 signaling pathway. Taken together, these findings indicated that berberine had the potential to ameliorate two major pathological manifestations of AD mainly by suppressing ER stress. Our work provided knowledge on the pharmacological intervention of AD and the possible targets for future drug development.
阿尔茨海默病（AD）与内质网应激（ER应激）密切相关，内质网应激会加剧AD的两个主要病理表现：老年斑和神经原纤维缠结。黄连素广泛应用于多种疾病的临床治疗，据报道具有抗AD作用。在本研究中，黄连素被证明可改善APP/PS1小鼠的内质网应激和认知障碍。我们发现内质网应激作为信号转导的中心枢纽发挥作用，糖原合酶激酶3β（GSK3β）过度激活使tau磷酸化以及蛋白激酶R样内质网激酶（PERK）随后激活使真核翻译起始因子-2α（eIF2α）磷酸化证明了这一点。此外，eIF2α调节β-位点APP裂解酶-1（BACE1）的表达，BACE1将APP裂解为前寡聚化淀粉样β42（Aβ），即老年斑的主要成分，这通过使用靶向eIF2α的小干扰RNA得到证实。从机制上讲，黄连素可降低GSK3β活性，导致tau磷酸化下调。黄连素还通过抑制PERK/eIF2α/BACE1信号通路抑制Aβ生成。综上所述，这些发现表明黄连素有可能主要通过抑制内质网应激来改善AD的两个主要病理表现。我们的工作为AD的药理干预及未来药物开发的可能靶点提供了知识。
