miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

查看全文 作　　者：Man [1]Luo;Yayan [1]Pang;Junjie [1]Li;Lilin [1]Yi;Bin [1]Wu;Qiuyun [1]Tian;Yan [1]He;Maoju [1]Wang;Lei [1]Xia;Guiqiong [2]He;Weihong [1,3,4]Song;Yehong [1]Du;Zhifang [1,5]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,China;[2]Department of Anatomy,Basic Medical College,Chongqing Medical University,Chongqing 400016,China;[3]Townsend Family Laboratories,Department of Psychiatry,The University of British Columbia,Vancouver BC V6T 1Z3,Canada;[4]Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health),Institute of Aging,Key Laboratory of Alzheimer’s Disease of Zhejiang Province,Zhejiang Clinical Research Center for Mental Disorders,School of Mental Health and the Affiliated Kangning Hospital,Wenzhou Medical University,Wenzhou 325000,China;[5]Institute for Brain Science and Disease of Chongqing Medical University,Chongqing 400016,China

出　　处：《Acta Pharmaceutica Sinica B》索引2024年第14卷第2期,共18页

基　　金：supported by grants from the National Natural Science Foundation of China (32371030, 82371194, 82071395 and 82001158);the Natural Science Foundation of Chongqing(CSTB2022NSCQ-LZX0010 and cstc2021ycjh-bgzxm0186, China);the Scientific and Technological Innovation Project for the Construction of Chengdu-Chongqing Economic Circle (KJCX ZD2020021, China);CQMU Program for Youth Innovation in Future Medicine (W0044, China) 摘　　要：Alzheimer ’s disease(AD) is a leading cause of dementia in the elderly.Mitogen-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in AD.However,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA translation.Here,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model cells.We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation.More importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment. 关键词：Alzheimer's disease MKP-1 miR-429-3p AMPAreceptor Learning and memory Long-term potentiation

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miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

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