首页|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
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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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 mech-anisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miR-NAs)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 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 conse-quently 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 potenti-ation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated ki-nase(ERKl/2)-mediated GluA1 hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluA1-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.
Alzheimer's diseaseMKP-1miR-429-3pAMPA receptorLearning and memoryLong-term potentiation
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
Department of Anatomy,Basic Medical College,Chongqing Medical University,Chongqing 400016,China
Townsend Family Laboratories,Department of Psychi
Institute for Brain Science and Disease of Chongq
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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Chongqing,ChinaNatural Science Foundation of Chongqing,ChinaNatural Science Foundation of Chongqing,ChinaScientific and Technological Innovation Project for the Construction of Chengdu-Chongqing Economic Circle,ChinaCQMU Program for Youth Innovation in Future Medicine,China
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