Insights into TREM2 biology by network analysis of human brain gene expression data
Open accessAbstract
Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes.
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A role of TREM2 in phagocytic pathways in the human brain was previously suggested.
“A role of TREM2 in phagocytic pathways in the human brain was previously suggested [13].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [13]
In the context of microglia, the kinase responsible for phosphorylating the ITAM residues on DAP12 is likely to be Src or a Src-family kinase such as Lyn.
“In the context of microglia, the kinase responsible for phosphorylating the Immunoreceptor Tyrosine Activation Motif (ITAM) residues on DAP12 is likely to be Src [62] or a Src-family kinase such as Lyn [63, 64].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [63]
Forabosco and colleagues used network analysis to explore TREM2 function, suggesting a role for microglial function and implicating neuroinflammation in Alzheimer disease.
“Forabosco and colleagues152 used network analysis to explore the function of TREM2 (triggering receptor expressed on myeloid cells 2), an Alzheimer disease risk gene, suggesting a role for microglial function and further implicating neuroinflammation in Alzheimer disease.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [152]
The network identified is broadly similar to a human network of innate immune genes containing TYROBP, TREM2, MS4A family genes, C1Q members and CD33, identified from human post-mortem tissue.
“The network we identified is also broadly similar to a human network of innate immune genes containing TYROBP, TREM2, MS4A family genes, C1Q members and CD33, identified from human post-mortem tissue bearing in mind the caveats discussed above for human tissue (Forabosco et al., 2013; Zhang et al., 2013).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Forabosco et al., 2013
The transcriptional network associated with amyloid identified in this analysis, containing the four predicted risk genes and the seven existing GWAS loci, is broadly similar to microglial networks previously identified in human brain analyses.
“Aspects of the transcriptional network associated with amyloid that we identified in our analysis, containing the four predicted risk genes with the existing seven GWAS loci, are broadly similar to microglial networks we and others have previously identified in human brain analyses.”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Forabosco et al., 2013
The authors previously described a human microglial network containing LAPTM5, ITGAM/CD11b and LILRB4.
“we described a human microglial network containing LAPTM5, ITGAM/CD11b and LILRB4 (Forabosco et al., 2013)”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Forabosco et al., 2013
TREM2 expression is increased in the cognitively normal aged brain.
“TREM2 expression is increased in the cognitively normal aged brain [43].”
From Microglial dysfunction in brain aging and Alzheimer's disease (2014) · cites this paper as [43]
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References 72 · Cited by 180
- Authors
- Forabosco, P., Ramasamy, A., Trabzuni, D., Walker, R., Smith, C., Bras, J., Levine, A. P., Hardy, J., Pocock, J. M., Guerreiro, R., Weale, M. E., & Ryten, M.
- Affiliations
- National Research Council (IT)
- Guy's Hospital (GB)
- King Faisal Specialist Hospital & Research Centre (SA)
- University of Edinburgh (GB)
- University College London (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Ryten, Mina
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 34
- Issue
- 12
- Pages
- 2699-2714
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3988951
- OpenAlex
- W2095565380
- Cited by
- 180
- References
- 72
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 5 · 2022: 18 · 2021: 22 · 2020: 20 · 2019: 11 · 2018: 17 · 2017: 11 · 2016: 16 · 2015: 14 · 2014: 15 · 2013: 6
- FWCI
- 9.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- MRC (G0901254, G0802462)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- TREM2, late-onset Alzheimer's disease, microglia, gene co-expression network, hub genes, hippocampus, phagocytosis, microglial migration, innate immunity, adaptive immunity, multiple sclerosis, motor neuron disease, disease-associated genes
- MeSH terms
- Alzheimer Disease, Brain, Humans, Immunity, Innate, Membrane Glycoproteins, Multiple Sclerosis, Phagocytosis, Receptors, Immunologic, Genetic Variation, Gene Expression, Motor Neuron Disease, Microglia, Genetic Predisposition to Disease, Protein Array Analysis, Adaptive Immunity
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