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. 2023 Jul 19;26(3):426.
doi: 10.3892/etm.2023.12125. eCollection 2023 Sep.   eCollection 2023 年 9 月。

lncRNA and circRNA expression profiles in the hippocampus of Aβ25‑35‑induced AD mice treated with Tripterygium glycoside
Aβ 25‑35 ‑诱导的阿尔茨海默病小鼠海马中 Tripterygium glycoside 处理的 lncRNA 和 circRNA 表达谱

Liang Tang  1   2   3   4 , Yan Wang  1   2   3 , Ju Xiang  1   3   4 , Dawei Yang  1   3   4 , Yan Zhang  1   3   4   5 , Qin Xiang  1   3   4 , Jianming Li  1   3   4
梁唐   1   2   3   4 , 燕王   1   2   3 , 巨香   1   3   4 , 大伟杨   1   3   4 , 燕张   1   3   4   5 , 秦香   1   3   4 , 建明李   1   3   4
Affiliations   隶属关系

lncRNA and circRNA expression profiles in the hippocampus of Aβ25‑35‑induced AD mice treated with Tripterygium glycoside

Liang Tang et al. Exp Ther Med. .

Abstract   摘要

Tripterygium glycosides (TG) have been reported to ameliorate Alzheimer's disease (AD), although the mechanism involved remains to be determined. In the present study, the lncRNA and circRNA expression profiles of an AD mouse model treated with TG were assessed using microarrays. lncRNAs, mRNAs, and circRNAs in the hippocampi of 3 AD+normal saline (NS) mice and 3 AD+TG mice were detected using microarrays. The most differentially expressed lncRNAs, mRNAs, and circRNAs were screened between the AD+NS and AD+TG groups. The differentially expressed lncRNAs and circRNAs were analyzed using GO enrichment and KEGG analyses. Co-expression analysis of lncRNAs, circRNAs, and mRNAs was performed by calculating the correlation coefficients. Protein-protein interaction (PPI) network analysis was performed on mRNAs using STRING. The lncRNA-target-transcription factor (TF) network was analyzed using the Network software. In total, 661 lncRNAs, 64 circRNAs, and 503 mRNAs were found to be differentially expressed in AD mice treated with TG. Pou4f1, Egr2, Mag, and Nr4a1 were the hub genes in the PPI network. The KEGG results showed that the mRNAs that were co-expressed with lncRNAs were enriched in the TNF, PI3K-Akt, and Wnt signaling pathways. LncRNA-target-TF network analysis indicated that TFs, including Cebpa, Zic2, and Rxra, were the most likely to regulate the detected lncRNAs. The circRNA-miRNA interaction network indicated that 275 miRNAs may bind to the 64 circRNAs. In conclusion, these findings provide a novel perspective on AD pathogenesis, and the detected lncRNAs, mRNAs, and circRNAs may serve as novel therapeutic targets for the management of AD.
三萜苷（TG）已被报道可以改善阿尔茨海默病（AD），尽管相关机制尚待确定。在本研究中，使用微阵列评估了 TG 处理的 AD 小鼠模型的 lncRNA 和 circRNA 表达谱。通过微阵列检测了 3 只 AD+生理盐水（NS）小鼠和 3 只 AD+TG 小鼠海马中的 lncRNA、mRNA 和 circRNA。筛选出 AD+NS 组和 AD+TG 组之间表达差异最大的 lncRNA、mRNA 和 circRNA。使用 GO 富集和 KEGG 分析对差异表达的 lncRNA 和 circRNA 进行了分析。通过计算相关系数对 lncRNA、circRNA 和 mRNA 进行了共表达分析。使用 STRING 对 mRNA 进行了蛋白质-蛋白质相互作用（PPI）网络分析。使用 Network 软件分析了 lncRNA-靶标-转录因子（TF）网络。总共发现 661 个 lncRNA、64 个 circRNA 和 503 个 mRNA 在 TG 处理的 AD 小鼠中表达差异。Pou4f1、Egr2、Mag 和 Nr4a1 是 PPI 网络中的核心基因。 KEGG 结果显示，与 lncRNA 共同表达的 mRNA 在 TNF、PI3K-Akt 和 Wnt 信号通路中富集。LncRNA-靶标-TF 网络分析表明，包括 Cebpa、Zic2 和 Rxra 在内的 TF 最有可能调控检测到的 lncRNA。circRNA-miRNA 相互作用网络表明，275 个 miRNA 可能与 64 个 circRNA 结合。总之，这些发现为 AD 发病机制提供了新的视角，检测到的 lncRNA、mRNA 和 circRNA 可能作为 AD 管理的新治疗靶点。

Keywords: Alzheimer's disease; Tripterygium glycoside; circRNA; lncRNA.
关键词：阿尔茨海默病；雷公藤苷；circRNA；lncRNA。

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Conflict of interest statement
利益冲突声明

The authors declare that they have no competing interests.
作者声明他们没有竞争利益。

Figures   数字

Figure 1
Figure 1
The hierarchical clustering of the DE lncRNAs, mRNAs, and circRNAs in AD (n=3/group) and AD treated with TG (n=3/group). Clustering analysis of the (A) DElncRNAs, (C) DEmRNAs and (E) DEcircRNAs. qPCR validation of 4 randomly selected (B) DElncRNAs, (D) DEmRNAs, and (F) DEcircRNAs. The qPCR results were consistent with the microarray data. **P<0.05. DE, differentially expressed; AD, Alzheimer's disease.
Figure 2
Figure 2
The top 20 lncRNA-mRNA interactions based on the network analysis. Red circles represent dysregulated lncRNAs, green squares represent dysregulated mRNAs.
Figure 3
Figure 3
The top 10 circRNA-mRNA interactions based on the network analysis. Yellow circles represent dysregulated circRNAs, red triangles represent dysregulated mRNAs.
Figure 4
Figure 4
Protein-protein interaction network based on the top 200 differentially expressed mRNAs.
Figure 5
Figure 5
KEGG pathway and GO enrichment analysis of differentially expressed lncRNAs. The top 30 most enriched GO categories and pathways were calculated and plotted. (A) GO enrichment analysis and (B) KEGG pathway analysis. KEGG, Kyoto encyclopedia of genes and genomes.
Figure 6
Figure 6
The trans- and cis- regulation of lncRNAs and genes. (A) the top 20 cis regulated lncRNAs and genes. mRNAs and lncRNAs are shown on the left and right Y-axis respectively. The X-axis shows the distance between the mRNA and lncRNA in the genome; negative values represent an upstream position and positive value represent a downstream position. Same colored bars represent the same lncRNAs. (B) The top 500 trans regulated lncRNAs and genes. The red node represents lncRNAs, the green node represents genes, and the node size represents connectivity (the number of connections of a node with other nodes). The larger the node size, the greater its connectivity. *P<0.05, **P<0.01.
Figure 7
Figure 7
lncRNA-target-TF network of the 2 most differently expressed lncRNAs. Red circles, lncRNAs; green squares, target mRNAs; purple triangles, TFs. TFs, transcription factors.
Figure 8
Figure 8
KEGG pathway and GO enrichment analysis of differently expressed circRNA host genes. The top 30 most enriched GO categories and pathways were calculated and plotted. (A) GO and (B) KEGG pathway enrichment analyses. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
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Grants and funding

Funding: This work was supported by the National Natural Science Foundation of China (grant no. 81873780), The Changsha Outstanding Innovative Young People Training Scheme (grant nos. kq2206058 and kq2206056), The Foundation of Project of Hunan Health and Family Planning Commission (grant no. 202202082739), The Foundation of the Education Department of Hunan Province (grant nos. 21A0586 and 22A0662), The Foundation of the Education Department of Guangxi Province (grant no. 2021KY1959); The Hunan Key Laboratory Cultivation Base of the Research and Development of Novel Pharmaceutical Preparations (grant no. 2016TP1029), and the Application Characteristic Discipline of Hunan Province.

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