Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease
Autor: | Zhongli Shi, Kaixia Zhang, Bing Xie, Rui Zhang, Huimin Zhou, Lei Jiang, Yajuan Yin, Dongsheng Cui, Zhaoyu Gao, Wenzhen Xia, Ruiyuan Wang, Shunjiang Xu |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Untranslated region Aging Morris water navigation task Hippocampus Pharmacology memory Mice chemistry.chemical_compound 0302 clinical medicine P53 protein 3' Untranslated Regions Aged 80 and over Neurons Neuronal Plasticity Alzheimer's disease Synaptotagmin I Female synaptotagmin 1 MAP Kinase Signaling System Biology Transfection SYT1 Synaptotagmin 1 03 medical and health sciences Alzheimer Disease microRNA Animals Humans Cognitive Dysfunction Antagomir RNA Messenger Aged miRNA Original Paper Binding Sites synaptic plasticity Antagomirs Cell Biology Disease Models Animal MicroRNAs HEK293 Cells 030104 developmental biology chemistry Synapses Synaptic plasticity Tumor Suppressor Protein p53 Reactive Oxygen Species Biomarkers 030217 neurology & neurosurgery |
Zdroj: | Aging Cell |
ISSN: | 1474-9726 1474-9718 |
Popis: | Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD. miR‐34c mediated synaptic plasticity deficits by targeting SYT1 through ROS‐JNK‐p53 pathway in response to oxidative stress and participated in the pathogenesis of AD. |
Databáze: | OpenAIRE |
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