Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis
Abstract
:1. Introduction: The Role of Microglia in Alzheimer’s Disease
2. Transcriptomic Networks to Understand Functional Gene-Gene Interactions in AD
2.1. Primers of Transcriptional Gene Networks
2.2. From Gene Co-Expression to Regulatory Networks in Disease
3. Advancements in Transcriptomics and Gene Network Analysis
3.1. Assessing the Transcriptome
3.2. Microarray-Based Network Analyses in AD
3.3. RNA-Seq-Based Studies in AD
3.4. Single-Cell RNA-Sequencing (scRNA-sequencing) in AD
4. Further Applications of Transcriptomic Gene Networks in AD
5. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
References
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Insights into AD Pathology | Technology | Species - Tissue type | Network Inference Method | References |
---|---|---|---|---|
-Upregulation of neural signaling elements and pro-inflammatory elements | Microarray | Human - Hippocampal CA1 | Cluster analysis | [78] |
-CD4, DCN, and IL8 extracellular ligands linked to disease initiation -Implication of miRNA-networks in AD pathogenesis | Microarray | Human - Hippocampal CA1 - Entorhinal Cortex | Network Topology Analysis | [82] |
-PSEN1 is strongly associated with myelin proteins -Conservation of modules for metabolism and synaptic plasticity conserved between AD and aging | Microarray | Human - Hippocampal CA1 | WGCNA | [88] |
-Apoe implicated as a general aging gene and associated with syndromic learning impairment | Microarray | Rat - Hippocampus | Ingenuity Pathway Analysis (IPA) | [83] |
-Cdk5r1, Dlg3, Kcnab2, and Mapk1, and Camk1g identified as hub network genes and associated with ion signaling and learning | Microarray | Rat - Hippocampus | WGCNA | [86] |
-TYROBP, PTPRC, ITGB2, and Trem2 identified as “hub” genes in AD gene networks in humans and mice, respectively -Conservation of genes across humans and mice AD | Microarray RNA-Seq | Human - Prefrontal Cortex - Substantia Nigra Mouse - Hippocampus | WGCNA | [91,92] |
-Role of splicing quantitative trait loci and co-splicing gene networks in AD -CLU, PICALM, and PTK2B show unique splicing mechanisms in AD | RNA-Seq | Human - Dorsolateral Prefrontal Cortex | WGCNA GeNets | [101,148] |
-PARK2 associated with NLRP3 inflammasome in microglia activation - 6 FDA-approved drugs (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat) predicted to modulate microglia master regulators | Microarray | Human - Hippocampus | ARACNE (Algorithm for the Reconstruction of Accurate Cellular Networks) | [63,64] |
-Role of splicing gene networks of microglia in AD, and identification of App and Clstn1 as differentially spliced -Splicing occurs differentially across different cell types in AD brain | RNA-Seq | Mouse - Cortex | WGCNA | [105] |
-Alternative exon-exon junction splicing in AD brain | RNA-Seq | Human - Dorsolateral Prefrontal Cortex | WGCNA | [107] |
-C3-C3ar signaling associated with viral-synapse loss and reactive astrocytes, and its downregulation reduces tau pathology -Spi1, Trem2, and Ms4a6a part of C3ar gene network | RNA-Seq | Human - Parahippocampal Gyrus Mice - Hippocampus | Correlation-based | [112] |
-TYROBP identified as a key regulator in a microglia module controlling phagocytosis -Different brain regions have different regulators -Functional gene networks identified for prefrontal cortex including complements and cytokine networks | RNA-Seq | Human - Dorsolateral Prefrontal Cortex - Visual Cortex - Cerebellum | Module Differential Connectivity (MDC) Causal probabilistic Bayesian | [120] |
-Dissection of Damage-Associated Microglia(DAM) into pro-inflammatory and anti-inflammatory modules | Microarray Nanostring | Mouse - Whole brain | WGCNA | [62] |
-Trem2 network becomes sparser with AD pathogenesis; specifically, genes that lost connectivity overlap with Trem1-dependent genes in monocytes | scRNA-seq | Mouse - Cortex - Hippocampus | Correlation-based | [135] |
-Identification of master microglia gene regulators including PU.1/Ets family of TFs, Nfkb, Irf, and AP-1/Maf -Microglia gene network upregulation in AD | scRNA-seq | Mouse - Cortex - Hippocampus | SCENIC (Single Cell Regulatory Network Inference and Clustering) | [132] |
-Identification of microglia immune network containing Mafb, Irf2, and Nfkb1 | scRNA-seq | Mouse - Brain | SCENIC | [139] |
-APOE, TREM2, MEF2C, and PICALM implicated in microglia gene-trait correlation modules | scRNA-seq | Human - Prefrontal Cortex | SOM (Self Organizing Maps) | [142] |
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Chew, G.; Petretto, E. Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis. Genes 2019, 10, 798. https://doi.org/10.3390/genes10100798
Chew G, Petretto E. Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis. Genes. 2019; 10(10):798. https://doi.org/10.3390/genes10100798
Chicago/Turabian StyleChew, Gabriel, and Enrico Petretto. 2019. "Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis" Genes 10, no. 10: 798. https://doi.org/10.3390/genes10100798