Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model
Open accessAbstract
BACKGROUND: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer's disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. METHODS: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks. RESULTS: Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer's, Parkinson's, and Huntington's diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks. CONCLUSION: This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insight into the molecular changes underlying microglia activation during tau mediated neurodegeneration.
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NF-κB activation and NLRP3-ASC are involved in tau-induced microglial inflammation.
“Although how tau activates microglia to induce inflammation is poorly understood, recent transcriptomic studies demonstrate a role for NF-κB activation and NLRP3-ASC in this process [424, 425].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [424]
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Sparse expression bases in cancer reveal tumor drivers
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Self-citation
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Research works printed but not linked: 1
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Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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Cellular Specificity of NF-κB Function in the Nervous System
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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
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Self-citationIntersection of pathological tau and microglia at the synapse
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Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease
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SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy
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- Authors
- Wang, H., Li, Y., Ryder, J. W., Hole, J. T., Ebert, P. J., Airey, D. C., Qian, H.-R., Logsdon, B., Fisher, A., Ahmed, Z., Murray, T. K., Cavallini, A., Bose, S., Eastwood, B. J., Collier, D. A., Dage, J. L., Miller, B. B., Merchant, K. M., O’Neill, M. J., & Demattos, R. B.
- Affiliations
- Eli Lilly (United States) (US)
- Sage Bionetworks (US)
- Eli Lilly (United Kingdom) (GB)
- AbbVie (Germany) (DE)
- Corresponding author
- Wang, Hong
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2018-12
- Volume
- 13
- Issue
- 1
- Pages
- 65-65
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC6296031
- OpenAlex
- W2905203258
- Cited by
- 83
- References
- 89
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 16 · 2023: 10 · 2022: 7 · 2021: 16 · 2020: 16 · 2019: 10 · 2018: 1
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (P30AG10161, R01AG36836, R01AG15819, R01AG17917, U01AG46152, R01AG30146, U01AG32984)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglial activation, tau pathology, Alzheimer's disease, rTg4510 mice, microglial transcriptome, temporal gene expression, NF-κB signaling, innate immunity, cytokine signaling, glutamatergic synapses, apolipoprotein E, TREM2, neurodegeneration, Parkinson's disease, Huntington's disease
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mice, Transgenic, Gene Expression, tau Proteins, Microglia, Genetic Predisposition to Disease, Gene Regulatory Networks
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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