Original Research ARTICLE
The transcriptional landscape of microglial genes in aging and neurodegenerative disease
- 1School of Medicine, University of California San Francisco, United States
Microglia, the brain-resident myeloid cells, are strongly implicated in Alzheimer’s disease (AD) pathogenesis by human genetics. However, the mechanisms by which microglial gene expression is regulated in a region-specific manner over the course of normal aging and in neurodegenerative disease are only beginning to be deciphered. Herein, we used a specific marker of microglia (TMEM119) and a cell-type expression profiling tool (CellMapper) to identify a human microglial gene expression module. Surprisingly, we found that microglial module genes are robustly expressed in several healthy human brain regions known to be vulnerable in AD, in addition to other regions affected only later in disease or spared in AD. Surveying the microglial gene set for differential expression over the lifespan in mouse models of AD and a related tauopathy revealed that the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status. Extending these results, we also observed significant upregulation of microglial module genes in several AD-affected brain regions in addition to other regions using postmortem brain tissue from human AD samples. In pathologically confirmed AD cases, we found preliminary evidence that microglial genes may be dysregulated in a sex-specific manner. Finally, we identified specific and significant overlap between the described microglial gene set—identified by unbiased co-expression analysis—and genes known to impart risk for AD. Our findings suggest that microglial genes show enriched expression in AD-vulnerable brain regions, are upregulated during aging and neurodegeneration in mice, and are upregulated in pathologically affected brain regions in AD. Taken together, our data-driven findings from multiple publicly accessible datasets reemphasize the importance of microglial gene expression alterations in AD and, more importantly, suggest that regional and sex-specific variation in microglial gene expression may be implicated in risk for and progression of neurodegenerative disease.
Keywords: Microglia, Alzheimer’s disease, mouse models, neurodegeneration, gene expression analsysis, TMEM119, TREM2, ALOX5AP, LAPTM5, C3, TASTPM, P301L, Aging, anova, human, Genetics, RNA
Received: 26 Dec 2018;
Accepted: 08 May 2019.
Edited by:Guillaume DOROTHEE, INSERM U938 Centre de Recherche Saint Antoine, France
Reviewed by:Delphine Boche, University of Southampton, United Kingdom
Sarah A. Gagliano Taliun, University of Michigan, United States
Copyright: © 2019 Bonham, Sirkis and Yokoyama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Jennifer S. Yokoyama, School of Medicine, University of California San Francisco, San Francisco, CA 94143, California, United States, Jennifer.Yokoyama@ucsf.edu