Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression
Inge R Holtman1, Divya D Raj2, Jeremy A Miller3
1Department of Neuroscience, section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. irholtman@gmail.com.
Introduction:
Microglia are tissue macrophages of the central nervous system that monitor brain homeostasis and react upon neuronal damage and stress. Aging and neurodegeneration induce a hypersensitive, pro-inflammatory phenotype, referred to as primed microglia. To determine the gene expression signature of priming, the transcriptomes of microglia in aging, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) mouse models were compared using Weighted Gene Co-expression Network Analysis (WGCNA).
Results:
A highly consistent consensus transcriptional profile of up-regulated genes was identified, which prominently differed from the acute inflammatory gene network induced by lipopolysaccharide (LPS). Where the acute inflammatory network was significantly enriched for NF-κB signaling, the primed microglia profile contained key features related to phagosome, lysosome, antigen presentation, and AD signaling. In addition, specific signatures for aging, AD, and ALS were identified.
Conclusion:
Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.
Insights
Microglia priming creates a consistent gene expression profile in aging and neurodegenerative diseases like Alzheimer's and ALS. This signature differs from acute inflammation and includes disease-specific changes.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are central nervous system macrophages crucial for brain homeostasis.
- Aging and neurodegeneration promote a pro-inflammatory state in microglia, termed 'priming'.
- Understanding the gene expression of primed microglia is vital for neurodegenerative disease research.
Purpose of the Study:
- To identify the gene expression signature of primed microglia.
- To compare transcriptional profiles across aging, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) models.
- To differentiate primed microglia profiles from acute inflammatory responses.
Main Methods:
- Weighted Gene Co-expression Network Analysis (WGCNA) was employed.
- Transcriptomes of microglia from aging, AD, and ALS mouse models were analyzed.
- Gene expression profiles were compared to lipopolysaccharide (LPS)-induced inflammation.
Main Results:
- A consistent, conserved transcriptional profile of up-regulated genes in primed microglia was identified.
- This profile significantly differed from the NF-κB signaling-enriched acute inflammatory network.
- Key features included pathways for phagosome, lysosome, antigen presentation, and AD signaling, with distinct signatures for aging, AD, and ALS.
Conclusions:
- Microglia priming results in a highly conserved transcriptional signature.
- This signature exhibits aging- and disease-specific characteristics.
- The findings provide insights into the molecular mechanisms of neuroinflammation.
