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Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis.

Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke EW, Eggen BJ - Acta Neuropathol Commun (2015)

Bottom Line: 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).In addition, specific signatures for aging, AD, and ALS were identified.Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. irholtman@gmail.com.

ABSTRACT

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.

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Related in: MedlinePlus

Summary figure describing the main findings of the current paper. Surveilling microglia are activated either acutely by a ligand such as LPS or by a neurodegenerative and aging brain environment.
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Fig6: Summary figure describing the main findings of the current paper. Surveilling microglia are activated either acutely by a ligand such as LPS or by a neurodegenerative and aging brain environment.

Mentions: Primed microglia are characterized by hypersensitive responses to proinflammatory stimuli. It has been suggested that priming of microglia is induced by chronic exposure to low-grade inflammation, as observed in neurodegenerative diseases and brain aging [9]. Microglia priming has been described to occur during aging and in a variety of CNS-diseases including AD, Parkinson’s disease, Multiple Sclerosis, ALS, stroke, Wallerian degeneration, and Me7 prion infection [43]. Furthermore, it is hypothesized that this hyper exaggerated responsiveness of the primed microglia contributes to the observed neurodegeneration [11]. The signaling pathways and mechanisms involved in the induction of priming are unknown. We therefore set out further to characterize the mechanisms of microglia priming using gene expression profiling in mouse models for aging and neurodegenerative disease. Using WGCNA we have identified specific gene expression networks associated with microglia priming. A visual summary of the main findings of this manuscript are depicted in Figure 6.Figure 6


Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis.

Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke EW, Eggen BJ - Acta Neuropathol Commun (2015)

Summary figure describing the main findings of the current paper. Surveilling microglia are activated either acutely by a ligand such as LPS or by a neurodegenerative and aging brain environment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4489356&req=5

Fig6: Summary figure describing the main findings of the current paper. Surveilling microglia are activated either acutely by a ligand such as LPS or by a neurodegenerative and aging brain environment.
Mentions: Primed microglia are characterized by hypersensitive responses to proinflammatory stimuli. It has been suggested that priming of microglia is induced by chronic exposure to low-grade inflammation, as observed in neurodegenerative diseases and brain aging [9]. Microglia priming has been described to occur during aging and in a variety of CNS-diseases including AD, Parkinson’s disease, Multiple Sclerosis, ALS, stroke, Wallerian degeneration, and Me7 prion infection [43]. Furthermore, it is hypothesized that this hyper exaggerated responsiveness of the primed microglia contributes to the observed neurodegeneration [11]. The signaling pathways and mechanisms involved in the induction of priming are unknown. We therefore set out further to characterize the mechanisms of microglia priming using gene expression profiling in mouse models for aging and neurodegenerative disease. Using WGCNA we have identified specific gene expression networks associated with microglia priming. A visual summary of the main findings of this manuscript are depicted in Figure 6.Figure 6

Bottom Line: 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).In addition, specific signatures for aging, AD, and ALS were identified.Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. irholtman@gmail.com.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus