Analysis Of LncRNA And MRNA Expression Profiles And Regulatory Networks In Brain Tissue Of Alzheimer’s Disease Mice

Objective: The role of non-coding RNA(nc RNA)in the pathogenesis of Alzheimer’s disease(AD)is still unclear.In this study,we screened the long non-coding RNA()and messenger RNA(m RNA)differentially expressed in the brain tissue of APP/PS1 transgenic AD mice and wild-type C57 mice by gene microarray technology.To analyze the possible regulatory mechanisms of differentially expressed m RNAs in AD and the biological functions of differentially expressed s and the signaling pathways involved.To find the s that may be related to the pathogenesis of AD.Construct a competitive endogenous RNA(ce RNA)regulatory network to explore the potential mechanisms of non-coding RNAs in AD,and to provide experimental and theoretical basis for the prevention and treatment of AD.Methods: Ten 10-month-old male APP/PS1 transgenic mice were selected as the AD group,and 10 age-and body mass-matched wild-type C57 mice were selected as the control group.(1)The cognitive functions of the mice in the two groups were examined by Morris water maze experiment,and the expression of Aβ in the hippocampus and cortical areas of the mice in the two groups were examined by immunohistochemistry.(2)The differential expression profiles of and m RNA in the brain tissues of the two groups of mice were analyzed according to the screening criteria of P < 0.05 and Fold change(FC)≥ 1.5 using gene microarray technology.(3)Seven significantly differentially expressed s were selected and validated by quantitative real-time PCR(q RT-PCR)in the brain tissues of the two groups of mice.(4)Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed on the differentially expressed m RNAs to explore the possible regulatory mechanisms of differentially expressed genes in AD.(5)Cis-target gene prediction of differentially expressed s and GO and KEGG enrichment analysis of their target genes were performed to analyze the possible biological functions and signaling pathways involved in differentially expressed s.(6)Six AD-related differentially expressed s were selected to construct the ce RNA regulatory network.Find the regulatory relationships of s in the ce RNA network.GO and KEGG enrichment analysis of ce RNA-regulated m RNAs were performed to explore the role of the -mi RNA-m RNA axis regulated by differentially expressed s in AD occurrence.Results:(1)APP/PS1 transgenic AD mice showed decreased cognitive function and increased Aβ plaque deposition in the brain.(2)Gene microarray results showed that a total of 933 differentially expressed s(222 up-regulated and 711down-regulated)and a total of 529 differentially expressed m RNAs(189 up-regulated and 340 down-regulated)were found in the brain tissue of AD mice compared with the control group.(3)q RT-PCR verified that the expression of s was consistent with the microarray sequencing results,which proved that the gene microarray detection results were reliable.(4)GO and KEGG enrichment analysis of differentially expressed m RNAs showed that differentially expressed genes were mainly enriched in signaling pathways such as amino acid metabolism and immune inflammatory response.(5)GO and KEGG enrichment analysis of differentially expressed target genes showed that differentially expressed target genes were mainly enriched in immune inflammatory response,cellular senescence and autophagy regulation.(6)The ce RNA regulatory network of AD-related s: Svip,AK034056,AW112010,AK132726,Nhsl2 and Dgkβ was successfully constructed.GO and KEGG enrichment analysis of the ce RNA predicted target genes revealed significant enrichment in immune inflammatory response and its related pathways,and the enriched genes were mainly CD86,H2-Q1 and Cxcr3.Lnc RNA-mi RNA-m RNA axis regulating CD86,H2-Q1 and Cxcr3 were found in the ce RNA network,including AW112010-mi R-1960-CD86/H2-Q1 axis and AW112010-mi R-329-59-Cxcr3 axis,and the above regulatory relationships may play an important role in the immune inflammatory mechanisms of AD development.Conclusions:(1)We screened the differentially expressed s and m RNAs in the brain tissue of AD mice,and the dysregulated s(933)and m RNAs(529)showed significant differential expression between the AD and control groups,suggesting that these differential transcripts may be related to the pathogenesis of AD.(2)Functional enrichment analysis of differentially expressed m RNAs in brain tissues of AD mice revealed significant enrichment in amino acid metabolism and immune inflammatory response and their related pathways,suggesting that dysregulation of amino acid metabolism and immune inflammatory response are involved in the pathophysiological process of AD.(3)Functional enrichment analysis of GO and KEGG was performed on the target genes of differentially expressed s in the brain tissue of AD mice,and significant enrichment was found in the pathways related to cellular senescence,autophagy and immune inflammatory response,suggesting that differentially expressed s may play an important role in the mechanisms related to the development of AD by regulating the expression of their target genes through the above pathways.(4)We constructed a -mi RNA-m RNA ce RNA regulatory network in AD mouse brain tissue to explore the potential mechanisms of non-coding RNAs in AD development.Among the constructed ce RNA regulatory networks,the AW112010-mi R-1960-CD86/H2-Q1 axis and AW112010-mi R-329-59-Cxcr3 axis may be associated with the immune inflammatory response in AD development,and AW112010 is expected to be a new target for AD treatment.