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 ...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.展开更多
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)+1 种基金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)
文摘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.
