<i>miR-429-3p</i> mediates memory decline by targeting MKP-1 to reduce surface GluA1containing AMPA receptors in a mouse model of Alzheimer's disease

作者全名："Luo, Man; Pang, Yayan; Li, Junjie; Yi, Lilin; Wu, Bin; Tian, Qiuyun; He, Yan; Wang, Maoju; Xia, Lei; He, Guiqiong; Song, Weihong; Du, Yehong; Dong, Zhifang"

作者地址："[Luo, Man; Pang, Yayan; Li, Junjie; Yi, Lilin; Wu, Bin; Tian, Qiuyun; He, Yan; Wang, Maoju; Xia, Lei; Song, Weihong; Du, Yehong; Dong, Zhifang] Chongqing Med Univ, Key Lab Child Dev & Disorders, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Chongqing 400014, Peoples R China; [He, Guiqiong] Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing 400016, Peoples R China; [Song, Weihong] Univ British Columbia, Dept Psychiat, Townsend Family Labs, Vancouver, BC V6T 1Z3, Canada; [Song, Weihong] Wenzhou Med Univ, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Key Lab Alzheimers Dis Zhejiang Prov, Zhejiang Clin Res Ctr Mental Disorders,Sch Mental, Wenzhou 325000, Peoples R China; [Song, Weihong] Wenzhou Med Univ, Affiliated Kangning Hosp, Wenzhou 325000, Peoples R China; [Dong, Zhifang] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Du, YH; Dong, ZF (通讯作者)，Chongqing Med Univ, Key Lab Child Dev & Disorders, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Chongqing 400014, Peoples R China.; Dong, ZF (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China."

来源：ACTA PHARMACEUTICA SINICA B

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001171000400001

JCR分区：Q1

影响因子：14.7

年份：2024

卷号：14

期号：2

开始页：635

结束页：652

文献类型：Article

关键词：Alzheimer's disease; MKP-1; miR-429-3p; AMPA receptor; Learning and memory; Long-term potentiation

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 N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 30-untranslated region (30 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 Ab 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 GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing a-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. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)."

基金机构："National Natural Science Foundation of China [32371030, 82371194, 82071395, 82001158]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-LZX0010, cstc2021ycjh-bgzxm0186]; Scientific and Technological Innovation Project for the Construction of Chengdu -Chongqing Economic Circle [KJCX ZD2020021]; CQMU Program for Youth Innovation in Future Medicine [W0044]"

基金资助正文："This work was 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) and CQMU Program for Youth Innovation in Future Medicine (W0044, China) . We are grateful to other members in the Dong laboratory for the technical support and helpful suggestion."