Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy

Chen, Menglu; Hong, Chengyu; Tao, Yue; Li, Hongming; Duan, Ran; Hu, Wenbao; Cao, Jia; Wang, Zhenxing; Chen, Chun-Yuan; Hu, Xiaozhou; Wu, Ben; Liu, Haoming; Tan, Yuyong; Liu, Jianghua; Luo, Zhenguo; Zhang, Yan; Rao, Shan‐Shan; Luo, Mingjie; Yin, Hao; Wang, Yiyi; Xia, Kun; Tang, Siyuan; Xie, Hui; Liu, Zhengzhao

doi:10.7150/thno.47408

Cited by 107 publications

(63 citation statements)

References 51 publications

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“…In aged APP-PSEN1-SREBF2 mice, chronic cholesterol accumulation results in an age-dependent impairment of OPTN translocation to mitochondria, inhibiting mitophagosome formation ( Roca-Agujetas et al, 2021 ). APP/PS1 mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p, two microRNAs targeting autophagy receptors SQSTM1 and OPTN, respectively, and antagomirs at a late stage ( Chen et al, 2021 ). The function of UBQLN2 in the ubiquitin protease system was to direct misfolded or redundant proteins to the proteasome for degradation.…”

Section: Discussionmentioning

confidence: 99%

Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer’s Disease

Li¹,

Wang²,

Guo³

et al. 2021

Front. Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles which significantly affects people’s life quality. Recently, AD has been found to be closely related to autophagy. The aim of this study was to identify autophagy-related genes associated with the pathogenesis of AD from multiple types of microarray and sequencing datasets using bioinformatics methods and to investigate their role in the pathogenesis of AD in order to identify novel strategies to prevent and treat AD. Our results showed that the autophagy-related genes were significantly downregulated in AD and correlated with the pathological progression. Furthermore, enrichment analysis showed that these autophagy-related genes were regulated by the transcription factor myocyte enhancer factor 2A (MEF2A), which had been confirmed using si-MEF2A. Moreover, the single-cell sequencing data suggested that MEF2A was highly expressed in microglia. Methylation microarray analysis showed that the methylation level of the enhancer region of MEF2A in AD was significantly increased. In conclusion, our results suggest that AD related to the increased methylation level of MEF2A enhancer reduces the expression of MEF2A and downregulates the expression of autophagy-related genes which are closely associated with AD pathogenesis, thereby inhibiting autophagy.

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Section: Discussionmentioning

confidence: 99%

Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer’s Disease

Li¹,

Wang²,

Guo³

et al. 2021

Front. Neurosci.

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“…In our study, miR-331 could lead to autophagy of OSC while inhibition of miR-331 could suppress autophagy of OSC. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy [22]. It has been reported that cell proliferation was signi cantly reduced after transient transfection of miR-331-3p precursor in Urothelial Carcinoma [23].…”

Section: Discussionmentioning

confidence: 99%

Exosomal miR-331 from Chemoresistant Osteosarcoma Cells induced Chemoresistance through Autophagy

Zhao¹,

Zhao²,

Liu

et al. 2021

Preprint

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BackgroundOsteosarcoma (OS) is a highly malignant tumor. Improving chemotherapeutic resistance is very important to improve the survival rate of OS. Exosomes and microRNAs (MiRNA) play important roles in the mechanism of chemotherapeutic resistance transmission. More and more researches focus the mechanism of miRNAs carried by exosomes in the transmission of chemotherapeutic resistance of OS. This study focused on exploring the mechanism of exosomal miR-331 in the transmission of chemoresistance in OS.MethodsWe cultured OS drug-resistant cells and extracted exosomes of these cells. The secretion and uptake of exosomes in OS drug-resistant cells and OS cells (OSCs) were confirmed by fluorescence tracking assay and transwell experiments. The differential expression of microRNA-331 (miR-331) in exosomes of OS resistant and OS cells was investigated by RT-PCR. The effects of drug-resistant exosomes on proliferation and migration of OS cells were determined by MTT assay and scratches assay. MDC staining, RT-PCR, and Western blot were used to detect the role of autophagy which regulated by drug-resistant cell-derived exosom-miR-331.ResultsWe found that the expression difference of miR-331 between MG63/CDDP and MG63 was the most significant. Drug resistant OSCs secreted exosomes and were ingested by OSCs, which then promoted OSCs to acquire drug resistance. In addition, exosomes secreted by drug-resistant OSCs promote drug resistance by carrying miRNAs. Interestingly, inhibition of miRNA resulted in reduced drug resistance transmission of exosomes. Finally, we found that the exosomes secreted by drug-resistant OSCs could induce autophagy of OSCs by carrying miR-331, thus making OSCs acquire drug resistance. Inhibition of miR-331 can effectively improve drug resistance of OSCs.ConclusionsChemoresistant OSCs-derived exosomes promote the transmission of drug resistance by carrying miR-331 and inducing autophagy. Inhibition of miR-331 could effectively alleviate drug resistance of OSCs.

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“…Nevertheless, leveraging the plethora of biological data generated by high-throughput RNA sequencing techniques in recent years, MOs provide us with insights into the effects of spatiotemporal dysregulations in complex gene expression networks on other prion-like diseases. For example, RNA sequencing data of AD mice revealed that miR-331-3p and miR-9-5p are upregulated at the late stage of the disease, but not at the early one [ 90 ]. In this regard, this same research group decided to determine the effects of inhibiting these two miRNAs in AD mice.…”

Section: Mirna-based Therapeuticsmentioning

confidence: 99%

“…Behavioral observations indicated that synergistic treatment of miR-331-3p and miR-9-5p antagomiRs might ameliorate memory loss and mobility/cognitive decline in AD mice. Moreover, compared with the control group, antagomiR-treated mice showed lower levels of Aβ along with higher levels of BECN1, OPTN, SQSTM1, and the ratio of LC3B-II:I, suggesting that miR-331-3p and miR-9-5p antagomiRs can reduce Aβ accumulation by enhancing autophagy activity [ 90 ]. Therefore, this study clearly shows how miRNA inhibition may be an upcoming strategy in clinical studies and applications in classic prion diseases in the future.…”

Section: Mirna-based Therapeuticsmentioning

confidence: 99%

MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine

Contiliani

Ribeiro

Moraes

et al. 2021

Cells

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MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions.

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Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy

Cited by 107 publications

References 51 publications

Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer’s Disease

Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer’s Disease

Exosomal miR-331 from Chemoresistant Osteosarcoma Cells induced Chemoresistance through Autophagy

MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine

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