MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models  

作　　者：Yehong Du Yexiang Du Yun Zhang Zhilin Huang Min Fu Junjie Li Yayan Pang Peng Lei Yu Tian Wang Weihong Song Guiqiong He Zhifang Dong 

机构地区：[1]Pediatric Research Institute,Ministry of Education Key Laboratory of Child Development and Disorders,National Clinical Research Center for Child Health and Disorders,China International Science and Technology Cooperation Base of Child Development and Critical Disorders,Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders,Children’s Hospital of Chongqing Medical University,Chongqing,400014,PR China [2]Department of Anatomy,Basic Medical College,Chongqing Medical University,Chongqing,400016,PR China [3]Townsend Family Laboratories,Department of Psychiatry,The University of British Columbia,Vancouver,BC,V6T 1Z3,Canada [4]West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,610041,Sichuan,China [5]Brain Research Centre,The University of British Columbia,Vancouver,BC,V6T 2B5,Canada

出　　处：《Signal Transduction and Targeted Therapy》2019年第1期149-160,共12页信号转导与靶向治疗（英文）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(NSFC)(grant no.91749116,81622015,81671257,and 81571042);the National Basic Research Program of China(grant no.2014CB548100);the Science and Technology Research Program of Chongqing Municipal Education Commission(grant no.KJZD-K201900403);the Innovation Research Group at Institutions of Higher Education in Chongqing(grant no.CXQTP19019019034).

摘　　要：Mitogen-activated protein kinase(MAPK)phosphatase 1(MKP-1)is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues.Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease(AD).However,the role of MKP-1 in AD pathogenesis remains elusive.Here,we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model.The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1(Sp1)cis-acting binding elements in the MKP-1 gene promoter.Amyloid-β(Aβ)-induced Sp1 activation decreased MKP-1 expression.However,upregulation of MKP-1 inhibited the expression of both Aβprecursor protein(APP)andβ-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2(ERK)/MAPK signaling pathway.Furthermore,upregulation of MKP-1 reduced Aβproduction and plaque formation and improved hippocampal long-term potentiation(LTP)and cognitive deficits in APP/PS1 transgenic mice.Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD,whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes.Thus,this study suggests that MKP-1 is a novel molecule for AD treatment.

关 键 词：ALZHEIMER AΒ IMPAIRMENT 

分 类 号：R73[医药卫生—肿瘤]