Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Abstract

Microglia, the main immune cells of the central nervous system, are increasingly implicated in Alzheimer’s disease (AD). Manifold transcriptomic studies in the brain have not only highlighted microglia’s role in AD pathogenesis, but also mapped crucial pathological processes and identified new therapeutic targets. An important component of many of these transcriptomic studies is the investigation of gene expression networks in AD brain, which has provided important new insights into how coordinated gene regulatory programs in microglia (and other cell types) underlie AD pathogenesis. Given the rapid technological advancements in transcriptional profiling, spanning from microarrays to single-cell RNA sequencing (scRNA-seq), tools used for mapping gene expression networks have evolved to keep pace with the unique features of each transcriptomic platform. In this article, we review the trajectory of transcriptomic network analyses in AD from brain to microglia, highlighting the corresponding methodological developments. Lastly, we discuss examples of how transcriptional network analysis provides new insights into AD mechanisms and pathogenesis.

Defining activation states of microglia in human brain tissue: an unresolved issue for Alzheimer’s disease

“…There are now enormous amounts of data available online for carrying out analyses using various statistical criteria to identify the interactions of expressed microglial genes. For a more detailed understanding of these analytical approaches, the review of Chew and Petretto provides an overview of the different analytical approaches focusing on how the identification of transcriptional networks of microglia in AD can give insight into disease pathogenesis [10] . One observation by these authors was the lack of agreement between studies on which genes/markers should be the targets for tissue validation.…”

“…Demonstration of cytokines IL-1α, IL-1β and TNF-α in AD brain microglia has been reported but these are not widely-used markers for describing microglia in tissue [52][53][54][55] . There appears to be technical difficulties in localizing these secreted cytokines in tissue, and it should be noted that these classical cytokines do not prominently feature in the microglial disease-associated gene signatures of recent studies [10,11,24,32] . In the paper of Friedman et al [24] , they provide supplementary data from gene expression profiles of two studies comparing control and AD samples; neither of these detected increased expression of these classical cytokines in AD samples (supplementary data file in reference [24] ).…”

“…The focus of this review will be on studies relating to AD, but many of the concepts might be applicable to PD, multiple sclerosis (MS) or stroke. The aim for this review is to bridge the gap between the studies that have analyzed transcription in large numbers of samples or isolated cells with in situ studies in human brain samples with antibodies to define the microenvironments of microglia in the specialized neuroanatomy of the human brain [10][11][12] . Ultimately, the best way to define the microglia responsible for damaging inflammation in brain samples will be with a single or small panel of markers that can be studied reliably in widely available types of pathological brain samples.…”

Precision and Personalized Medicine: How Genomic Approach Improves the Management of Cardiovascular and Neurodegenerative Disease

“…In this context, NGS technologies, by allowing for collecting a huge amount of digital genetic data, can help to define not only the complete molecular signatures of the disease, but also the cascade of events that induce or maintain such signatures. For example, differential transcriptome analyses of pathological vs. healthy brain tissue allow for the examination of protein-coding genes, non-coding RNAs or splicing events that are differentially expressed in the two conditions [74][75][76][77]. Thanks to the combination of all these data, it is possible to provide an "omic" profile of the patients, discover networks and possibly contribute to better understand the neurological disease mechanisms at 360 • .…”

Therapeutic Potential of Porcine Liver Decomposition Product: New Insights and Perspectives for Microglia-Mediated Neuroinflammation in Neurodegenerative Diseases

“…Many groups have clearly demonstrated the close spatial–temporal relationship network between amyloid fibrils and activated microglia in both Alzheimer’s disease patients and animal models [ 19 , 20 , 21 ]. Several studies have also indicated that Alzheimer’s risk genes determine the microglial response to amyloid-β precursor protein but not to Tau pathology using single microglia sequencing [ 22 , 23 ]. These results suggest that microglia are associated with the progression of Alzheimer’s disease.…”