Dataset Information

Identification of the Role of miR-142-5p in Alzheimer's Disease by Comparative Bioinformatics and Cellular Analysis.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the formation of amyloid beta (A?) or tau protein aggregates, the hallmark of cognitive decline. MicroRNAs (miRNAs) have emerged as critical factors in neurogenesis and synaptic functions in the central nervous system (CNS). Recent studies have reported alterations in miRNA expression in patients with AD. However, miRNAs associated with AD varied with patient groups or experimental models, suggesting the need for a comparative study to identify miRNAs commonly dysregulated in diverse AD models. Here, we investigated the miRNAs that show dysregulated expression in two different human AD groups and mouse and cellular AD models. After selection of commonly dysregulated miRNAs in these groups, we investigated the pathophysiological significance of miR-142-5p in SH-SY5Y neuronal cells. We found that miR-142-5p was increased upon treatment with A? peptide 1-42 (A?42). Inhibition of miR-142-5p rescued the A?42-mediated synaptic dysfunctions, as indicated by the expression of postsynaptic density protein 95 (PSD-95). Among genes with decreased expression in A?42-treated SH-SY5Y cells, the predicted miR-142-5p target genes were significantly related with neuronal function and synapse plasticity. These findings suggest that dysregulation in miR-142-5p expression contributes the pathogenesis of AD by triggering synaptic dysfunction associated with A?42-mediated pathophysiology.

SUBMITTER: Song J

PROVIDER: S-EPMC5513939 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of the Role of miR-142-5p in Alzheimer's Disease by Comparative Bioinformatics and Cellular Analysis.

Song Juhyun J Kim Young-Kook YK Kim Young-Kook YK

Frontiers in molecular neuroscience 20170718

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the formation of amyloid beta (Aβ) or tau protein aggregates, the hallmark of cognitive decline. MicroRNAs (miRNAs) have emerged as critical factors in neurogenesis and synaptic functions in the central nervous system (CNS). Recent studies have reported alterations in miRNA expression in patients with AD. However, miRNAs associated with AD varied with patient groups or experimental models, suggesting the need ...[more]

PMID: 28769761

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Project description:Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ). Methods: The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2+) and activated microglia (CD68+IBA1+) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (Becn1, Sqstm1, LC3b) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined. Results: MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (Sqstm1) and Optineurin (Optn), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage. Conclusion: Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.

Project description:BackgroundTamoxifen is the first-line hormone therapy for estrogen receptor alpha positive (ERα+) breast cancer. However, about 40% of patients with ERα + breast cancer who receive tamoxifen therapy eventually develop resistance resulting in a poor prognosis. The aim of this study was to mine available data sets in the Gene Expression Omnibus (GEO) database, including in vitro (cell lines) and in vivo (tissue samples), and to identify all miRNAs associated with tamoxifen resistance (TamR) in breast cancer. Secondly, this study aimed to predict the key gene regulatory networks of newly found TamR-related miRNAs and evaluate the potential role of the miRNAs and targets as potential prognosis biomarkers for breast cancer patients.ResultMicroarray data sets from two different studies were used from the GEO database: 1. GSE66607: miRNA of MCF-7 TamR cells; 2. GSE37405: TamR tissues. Differentially expressed microRNAs (miRNAs) were identified in both data sets and 5 differentially expressed miRNAs were found to overlap between the two data sets. Profiles of GSE37405 and data from the Kaplan-Meier Plotter Database (KMPD) along with Gene Expression Profiling Interactive Analysis (GEPIA) were used to reveal the relationship between these 5 miRNAs and overall survival. The results showed that has-miR-542-5p was the only miRNA associated with overall survival of ERα + breast cancer patients who received adjuvant tamoxifen. Targets of has-miR-542-5p were predicted by miRanda and TargetScan, and the mRNA expression of the three 3 target gene, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Beta (YWHAB), Lymphocyte Antigen 9 (LY9), and Secreted Frizzled Related Protein 1 (SFRP1) were associated with overall survival in 2 different databases. Copy-number alterations (CNAs) of SFRP1 confer survival disadvantage to breast cancer patients and alter the mRNA expression of SFRP1 in cBioPortal database.ConclusionThis study indicates that miRNA has-miR-542-5p is associated with TamR and can predict prognosis of breast cancer patients. Furthermore, has-miR-542-5p may be acting through a mechanism involving the target genes YWHAB, LY9, and SFRP1. Overall, has-miR-542-5p is a predictive biomarker and potential target for therapy of breast cancer patients.

Dataset Information

Identification of the Role of miR-142-5p in Alzheimer's Disease by Comparative Bioinformatics and Cellular Analysis.

Publications

Identification of the Role of miR-142-5p in Alzheimer's Disease by Comparative Bioinformatics and Cellular Analysis.

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