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RNA sequencing analysis of miR-603 overexpression

ABSTRACT: Alzheimer’s disease (AD) is a serious neurodegenerative disease in which miRNAs have been linked to its pathogenesis. miR-603 is a primate-specific miRNA. Through ADNI data analysis, we found a SNP rs11014002 in pre-miR-603 which promotes the biogenesis of mature miR-603 is associated with AD risk. We further identified that LRPAP1, a protein which antagonizes the function of LRP1 in Aβ clearance and AD susceptibility, is a target gene of miR-603. Moreover, overexpression of miR-603 increased the protein level of LRP1, suggesting the protective role of miR-603 in AD. Both significant increase and loss of regulatory function of miR-603 hint the existence of a compensatory mechanism in hippocampus of AD subjects. Furthermore, we found that miR-603 could directly downregulate E2F1 and prevent cells from H2O2 induced-apoptosis. This work provides the first evidence that miR-603 may modulate AD susceptibility and the SNP rs11014002 (T-carrier genotype) might be a protective factor for AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68987 | GEO | 2015/05/18

SECONDARY ACCESSION(S): PRJNA284262

REPOSITORIES: GEO

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RNA sequencing analysis of miR-603 overexpression

Project description:Alzheimer’s disease (AD) is a serious neurodegenerative disease in which miRNAs have been linked to its pathogenesis. miR-603 is a primate-specific miRNA. Through ADNI data analysis, we found a SNP rs11014002 in pre-miR-603 which promotes the biogenesis of mature miR-603 is associated with AD risk. We further identified that LRPAP1, a protein which antagonizes the function of LRP1 in Aβ clearance and AD susceptibility, is a target gene of miR-603. Moreover, overexpression of miR-603 increased the protein level of LRP1, suggesting the protective role of miR-603 in AD. Both significant increase and loss of regulatory function of miR-603 hint the existence of a compensatory mechanism in hippocampus of AD subjects. Furthermore, we found that miR-603 could directly downregulate E2F1 and prevent cells from H2O2 induced-apoptosis. This work provides the first evidence that miR-603 may modulate AD susceptibility and the SNP rs11014002 (T-carrier genotype) might be a protective factor for AD. There are two groups: Negative Control and miR-603 overexpression. We performed experiments on HEK293 cell and Hela cell.

2015-05-18 | E-GEOD-68987 | biostudies-arrayexpress

Expression data from human blood samples

2010-11-17 | GSE25414 | GEO

CLUC CLUT DNA binding proteins

Project description:Alzheimers disease (AD) is the most common form of dementia in the elderly with no cure. Although huge efforts have been made to develop drugs for AD, most programs aimed for disease-modifying therapies have failed. Possible reasons for the high failure rate include insufficient understanding of mechanisms underlying AD pathogenesis. The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset AD. However, whether the CLU rs11136000 SNP is functional and what are molecular mechanisms underlying the risk effect of the CLU variant remain unknown. In this study, we identified the CLU rs11136000 SNP as a functional variant by CRIPSR/Cas9 knockout of the SNP. Moreover, by switching the risk C and the protective T alleles using CRISPR/Cas9 editing, we generated isogenic iPSCs with different alleles of the CLU rs11136000 SNP. Astrocytes derived from isogenic iPSCs carrying the C or T allele exhibited different CLU expression and differential inflammatory response. C/C astrocytes carrying two C alleles expressed higher level of CLU and exhibited elevated interferon (IFN) response and CXCL10 expression upon TNFalpha/IL1beta treatment. Furthermore, using human iPSC-derived astrocytes and OPCs co-cultured on nanofibers, we demonstrated that elevated CXCL10 expression in C/C astrocytes induced by TNFalpha/IL1beta led to inhibition of OPC proliferation and myelination. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk C allele carriers. This knowledge could help us to design more effective strategies to treat AD by targeting IFN response and CXCL10 that are upstream of myelination deficits, an early event in AD pathogenesis that proceeds before cognitive decline.

2022-01-07 | MSV000088660 | MassIVE

Homo sapiens

Project description:RNA sequencing analysis of miR-603 overexpression

| PRJNA284262 | ENA

Expression data from human blood samples

Project description:Genetic factors contribute to the development of ischemic stroke but their identity remains largely unknown. We tested the association with ischemic stroke of 210 single nucleotide polymorphisms (SNPs) associated with pathways functionally related to stroke. We observed an association between the rs7956957 SNP in LRP1 and next performed microarrays analysis in healthy individuals to investigate possible associations of LRP genotypes with the expression of other genes. Twelve blood samples were obtained from twelve different healthy subjects carrying different genotypes for the rs7956957 SNP of the LRP1 gene (GG, CG or CC). Blood was extracted from 12 subjects. EDTA tubes were centrifuged at 3500rpm for 15 min to obtain the white blood cell fraction and the samples were stored at -80ºC until RNA isolation. RiboPureTM -Blood kit from Ambion (Ambion, Woodward st. Austin, USA) was used to extract total RNA following manufacturer’s instructions. Globin RNA from erythrocytes that causes interference was extracted using the Globin-Clear kit (Ambion, Woodward st. Austin, USA).

2010-11-17 | E-GEOD-25414 | biostudies-arrayexpress

Human MDA-MB-231 breast cancer cells overexpressing miR-183-5p and its isomiRs

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2022-05-26 | PXD026763 | Pride

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice

Project description:Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn't affect the Aβ levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

2023-05-15 | GSE231985 | GEO

Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer’s disease

Project description:Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.

2025-07-25 | GSE273690 | GEO

Alzheimer’s Disease Protective Allele of CLU Promotes Neuron Excitability, Neuron-glia Lipid Transfer and Astrocytic Lipid Droplets via neuronal CLU

Project description:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.

2024-06-10 | GSE269153 | GEO

NOF vs. coCAF 7d

Project description:Campare the difference between pairwise NOF and coCAF tissues for three patients patient #603: NOF #603 vs coCAF #603 patient #609: NOF #609 vs coCAF #609 patient #612: NOF #612 vs coCAF #612

2012-01-27 | E-GEOD-35250 | biostudies-arrayexpress

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