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Multiple Transcriptomic Analyses Explore Potential Synaptic Biomarker Rabphilin-3A for Alzheimer's Disease

Nguyen, Doan Phuong Quy, Pham, Son, Jallow, Amadou Wurry, Ho, Nguyen-Tuong, Le, Bao, Quang, Hung Tran, Lin, Yi-Fang, Lin, Yung-Feng·2024·Scientific Reports
DOI 10.1038/s41598-024-66693-8PMC PMC11319786
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Figure 1 Data acquisition and overall workflow of the current study. (A) All public datasets were obtained from the Gene Expression Omnibus database. The microarray analysis utilized blood samples (GSE97760) and brain tissue from the hippocampus, superior frontal gyrus (GSE48350), and entorhinal cortex (GSE5281). Single-cell expression was examined using RNA sequencing for the superior frontal gyrus and entorhinal cortex (GSE147528), along with the hippocampus (GSE175814). (B) Schematic diagram summarizing the methodology outline of the study.
Figure 1 Data acquisition and overall workflow of the current study. (A) All public datasets were obtained from the Gene Expression Omnibus database. The microarray analysis utilized blood samples (GSE97760) and brain tissue from the hippocampus, superior frontal gyrus (GSE48350), and entorhinal cortex (GSE5281). Single-cell expression was examined using RNA sequencing for the superior frontal gyrus and entorhinal cortex (GSE147528), along with the hippocampus (GSE175814). (B) Schematic diagram summarizing the methodology outline of the study.CC BY-NC-ND · PubMed Central
Figure 2 Visualization of Differentially Expressed Genes and Corresponding Heatmaps among different AD datasets. (A–D) Volcano plots highlight the DEGs between AD and control groups in blood (GSE97760), superior frontal gyrus, hippocampus (GSE48350), and entorhinal cortex (GSE5281), respectively. (E–H) Corresponding heatmaps elucidate the expression profiles of the top 40 most variable DEGs among datasets.
Figure 2 Visualization of Differentially Expressed Genes and Corresponding Heatmaps among different AD datasets. (A–D) Volcano plots highlight the DEGs between AD and control groups in blood (GSE97760), superior frontal gyrus, hippocampus (GSE48350), and entorhinal cortex (GSE5281), respectively. (E–H) Corresponding heatmaps elucidate the expression profiles of the top 40 most variable DEGs among datasets.CC BY-NC-ND · PubMed Central
Figure 3 Functional Enrichment Characteristic of distinct AD dataset. (A) Dot plot displays the KEGG pathway analysis results in the DEGs of the blood dataset. (B) A gene set enrichment analysis of the blood dataset is presented. The top four upregulated signatures and four downregulated signatures are shown. (C) The Venn diagram illustrates the overlap between DEGs of three brain tissue datasets. (D) KEGG results of the intersection obtained from (C). (E) The heatmap shows the common upregulated pathways and downregulated pathways shared between the entorhinal cortex, hippocampus, and superior frontal gyrus. Numbers within the boxes represent the normalized enrichment score (NES) score, using GSEA analysis. Upregulations are color-coded in red, whereas downregulations are marked in blue. Permission has been obtained from Kanehisa laboratories for using KEGG pathway database25
Figure 3 Functional Enrichment Characteristic of distinct AD dataset. (A) Dot plot displays the KEGG pathway analysis results in the DEGs of the blood dataset. (B) A gene set enrichment analysis of the blood dataset is presented. The top four upregulated signatures and four downregulated signatures are shown. (C) The Venn diagram illustrates the overlap between DEGs of three brain tissue datasets. (D) KEGG results of the intersection obtained from (C). (E) The heatmap shows the common upregulated pathways and downregulated pathways shared between the entorhinal cortex, hippocampus, and superior frontal gyrus. Numbers within the boxes represent the normalized enrichment score (NES) score, using GSEA analysis. Upregulations are color-coded in red, whereas downregulations are marked in blue. Permission has been obtained from Kanehisa laboratories for using KEGG pathway database25CC BY-NC-ND · PubMed Central
Figure 4 Identification of AD-predictive significance genes across multiple datasets. (A) Workflow summarizing the identification of AD-predictive significance genes across multiple datasets. A total of 19 genes met the criteria and were subdivided into Up-AD common genes and Down-AD common genes. (B) Comprehensive AUC scores for each of the 19 genes in different AD datasets, including blood, hippocampus, superior frontal gyrus, and entorhinal cortex.
Figure 4 Identification of AD-predictive significance genes across multiple datasets. (A) Workflow summarizing the identification of AD-predictive significance genes across multiple datasets. A total of 19 genes met the criteria and were subdivided into Up-AD common genes and Down-AD common genes. (B) Comprehensive AUC scores for each of the 19 genes in different AD datasets, including blood, hippocampus, superior frontal gyrus, and entorhinal cortex.CC BY-NC-ND · PubMed Central
Figure 5 Cellular annotation of AD single-cell datasets. (A–C) Uniform manifold approximation and projection (UMAP) visualization of three different single-cell datasets obtained from the superior frontal gyrus (GSE147528), entorhinal cortex (GSE147528), and hippocampus (GSE175814). (D–F) Dot plots illustrate the expression level of canonical markers from different cell types, including SLC17A7 for Excitatory neuron, GAD1 for Inhibitory neuron, CLDN5 for Endothelial, MBP for Oligodendrocyte, DOCK8 for Microglia, GFAP for Astrocyte and PDGFRA for OPC. (G–I) Corresponding UMAPs of the brain regions depict the cellular distribution in different conditions, including Braak 0, Braak 2, and Braak 6 stages (superior frontal gyrus and entorhinal cortex datasets), as well as AD and control states (hippocampus dataset).
Figure 5 Cellular annotation of AD single-cell datasets. (A–C) Uniform manifold approximation and projection (UMAP) visualization of three different single-cell datasets obtained from the superior frontal gyrus (GSE147528), entorhinal cortex (GSE147528), and hippocampus (GSE175814). (D–F) Dot plots illustrate the expression level of canonical markers from different cell types, including SLC17A7 for Excitatory neuron, GAD1 for Inhibitory neuron, CLDN5 for Endothelial, MBP for Oligodendrocyte, DOCK8 for Microglia, GFAP for Astrocyte and PDGFRA for OPC. (G–I) Corresponding UMAPs of the brain regions depict the cellular distribution in different conditions, including Braak 0, Braak 2, and Braak 6 stages (superior frontal gyrus and entorhinal cortex datasets), as well as AD and control states (hippocampus dataset).CC BY-NC-ND · PubMed Central
Figure 6 Gene expression patterns and differential analysis in neuron cells across Braak stages and disease states. (A,C,E) Violin plots depicting the significant differences in gene expression levels of KCNQ2, RPH3A, SV2A and TMEM59L between Braak stages 0 and 2, Braak stages 0 and 6, and Braak stages 2 and 6 (entorhinal cortex and superior frontal gyrus) as well as between AD and control samples (hippocampus) among excitatory and inhibitory neurons. *p < 0.05, **p < 0.01, ****p < 0.0001. (B,D,F) Corresponding gene expression patterns of 4 selected genes plotted on the UMAP coordinates in entorhinal cortex, superior frontal gyrus and hippocampus, respectively. These genes exhibit cell-type specificity in excitatory and inhibitory neurons. The color intensity corresponds to the expression level, with a gradient scale ranging from low (blue) to high (red) expression.
Figure 6 Gene expression patterns and differential analysis in neuron cells across Braak stages and disease states. (A,C,E) Violin plots depicting the significant differences in gene expression levels of KCNQ2, RPH3A, SV2A and TMEM59L between Braak stages 0 and 2, Braak stages 0 and 6, and Braak stages 2 and 6 (entorhinal cortex and superior frontal gyrus) as well as between AD and control samples (hippocampus) among excitatory and inhibitory neurons. *p < 0.05, **p < 0.01, ****p < 0.0001. (B,D,F) Corresponding gene expression patterns of 4 selected genes plotted on the UMAP coordinates in entorhinal cortex, superior frontal gyrus and hippocampus, respectively. These genes exhibit cell-type specificity in excitatory and inhibitory neurons. The color intensity corresponds to the expression level, with a gradient scale ranging from low (blue) to high (red) expression.CC BY-NC-ND · PubMed Central
Figure 7 Functional pattern similarity among three brain tissue datasets. (A–C) Lollipop plots illustrating shared downregulated pathways, with at least one of KCNQ2, RPH3A, SV2A, and TMEM59L, in the entorhinal cortex, superior frontal gyrus, and hippocampus, respectively.
Figure 7 Functional pattern similarity among three brain tissue datasets. (A–C) Lollipop plots illustrating shared downregulated pathways, with at least one of KCNQ2, RPH3A, SV2A, and TMEM59L, in the entorhinal cortex, superior frontal gyrus, and hippocampus, respectively.CC BY-NC-ND · PubMed Central
Figure 8 The Sankey plot illustrates the participation of individual genes in specific pathways overlapped between the three brain tissue datasets, using bulk-seq data.
Figure 8 The Sankey plot illustrates the participation of individual genes in specific pathways overlapped between the three brain tissue datasets, using bulk-seq data.CC BY-NC-ND · PubMed Central
Figure 9 Expression level of RPH3A, KCNQ2, and SV2A in the hippocampus of wildtype (WT) and AD (3xTg-AD) mice. (A) Western blotting of 3 candidate proteins in mouse hippocampus brain regions, three mice in each group were examined. The samples derive from the same experiment and that gels/blots were processed in parallel. Original blots are presented in Supplementary Figs. S6–S8. (B) Bar graph demonstrates the statistical results of the Western blots in WT and 3xTg-AD groups. **p < 0.01.
Figure 9 Expression level of RPH3A, KCNQ2, and SV2A in the hippocampus of wildtype (WT) and AD (3xTg-AD) mice. (A) Western blotting of 3 candidate proteins in mouse hippocampus brain regions, three mice in each group were examined. The samples derive from the same experiment and that gels/blots were processed in parallel. Original blots are presented in Supplementary Figs. S6–S8. (B) Bar graph demonstrates the statistical results of the Western blots in WT and 3xTg-AD groups. **p < 0.01.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Nguyen, D. P. Q., Pham, S., Jallow, A. W., Ho, N.-T., Le, B., Quang, H. T., Lin, Y.-F., & Lin, Y.-F.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2024-08-12
Volume
14
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-024-66693-8
PMC
PMC11319786
Cited by
14
References
9
Language
en
Licence
Funders
Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare (112FRP-29)

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