SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway

作者全名：Xing, Dianxia; Zhang, Wenjin; Cui, Wei; Yao, Xiuya; Xiao, Yaping; Chen, Lihua; Yuan, Shiyun; Duan, Yanyan; Yu, Weihua; Pan, Pengfei; Lu, Yang

作者地址：[Xing, Dianxia; Chen, Lihua; Yuan, Shiyun; Lu, Yang] Chongqing Med Univ, Affiliated Hosp 1, Dept Geriatr, Chongqing, Peoples R China; [Xing, Dianxia] Chongqing Univ, Dept Geriatr, Three Gorges Hosp, Chongqing, Peoples R China; [Zhang, Wenjin; Cui, Wei; Yao, Xiuya] Chongqing Univ, Cent Lab, Three Gorges Hosp, Chongqing, Peoples R China; [Xiao, Yaping] Chongqing Univ, Dept Pharm & Pharmacol, Three Gorges Hosp, Chongqing, Peoples R China; [Duan, Yanyan] Chongqing Three Gorges Univ, Coll Biol & Food Engn, Chongqing, Peoples R China; [Yu, Weihua] Chongqing Med Univ, Inst Neurosci, Chongqing, Peoples R China; [Pan, Pengfei] Chongqing Univ, Intens Care Unit, Three Gorges Hosp, Chongqing, Peoples R China

通信作者：Lü, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Geriatr, Chongqing, Peoples R China.; Pan, PF (通讯作者)，Chongqing Univ, Intens Care Unit, Three Gorges Hosp, Chongqing, Peoples R China.

来源：AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001251972600003

JCR分区：Q1

影响因子：5

年份：2024

卷号：326

期号：6

开始页：C1697

结束页：C1709

文献类型：Article

关键词：Alzheimer's disease; apoptosis; mTOR; sirtuin 4; transcription factor STAT2

摘要：Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study used APP/PS1 mice as an animal model of AD and amyloid-beta (A beta)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine A beta deposition in mice and apoptosis, respectively. Protein expression was assessed by Western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of Sirt4. Subsequently, the binding of transcription factors to Sirt4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and A beta-treated HT-22 cells compared with their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased A beta deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.

基金机构：Science and Technology Bureau of Wanzhou, Chongqing

基金资助正文：We express our gratitude to the technical staff from Zhongshi Dichuang Technology Development Co., Ltd., Beijing, China, for their invaluable assistance and unwavering support throughout the behavioral experiments.