Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain
Open accessAbstract
The complement cascade not only provides protection from infection but can also mediate destructive inflammation. Complement is also involved in elimination of neuronal synapses which is essential for proper development, but can be detrimental during aging and disease. C1q, required for several of these complement-mediated activities, is present in the neuropil, microglia, and a subset of interneurons in the brain. To identify the source(s) of C1q in the brain, the C1qa gene was selectively inactivated in the microglia or Thy-1+ neurons in both wild type mice and a mouse model of Alzheimer’s disease (AD), and C1q synthesis assessed by immunohistochemistry, QPCR, and western blot analysis. While C1q expression in the brain was unaffected after inactivation of C1qa in Thy-1+ neurons, the brains of C1qa FL/FL :Cx3cr1 CreERT2 mice in which C1qa was ablated in microglia were devoid of C1q with the exception of limited C1q in subsets of interneurons. Surprisingly, this loss of C1q occurred even in the absence of tamoxifen by 1 month of age, demonstrating that Cre activity is tamoxifen-independent in microglia in Cx3cr1 CreERT2/WganJ mice. C1q expression in C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice continued to decline and remained almost completely absent through aging and in AD model mice. No difference in C1q was detected in the liver or kidney from C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice relative to controls, and C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice had minimal, if any, reduction in plasma C1q. Thus, microglia, but not neurons or peripheral sources, are the dominant source of C1q in the brain. While demonstrating that the Cx3cr1 CreERT2/WganJ deleter cannot be used for adult-induced deletion of genes in microglia, the model described here enables further investigation of physiological roles of C1q in the brain and identification of therapeutic targets for the selective control of complement-mediated activities contributing to neurodegenerative disorders.
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Microglial-expressed complement components including C1q bind to synapses and enable phagocytosis by microglia.
“microglial-expressed complement components, including C1q, are thought to bind to synapses and enable phagocytosis by microglia [75, 103]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [103]
Cx3cr1CreER mouse lines can induce loxP recombination in microglia in the absence of TAM.
“In certain cases, it has also been shown that Cx3cr1CreER mouse lines can induce loxP recombination in microglia in the absence of TAM.16–18”
From A comparative analysis of microglial inducible Cre lines (2023) · cites this paper as [16]
The iSuReCre allele is recombined by DCXCreER, similar to other Cre and CreER lines tested in the original publication, but is not recombined in adult microglia by P2ry12CreER.
“These data confirm that the iSuReCre allele is recombined by DCXCreER, similar to other Cre and CreER lines tested in the original publication20, but is not recombined in adult microglia by P2ry12CreER.”
From A comparative evaluation of the strengths and potential caveats of the microglial inducible CreER mouse models (2024) · cites this paper as [20]
The Methods (Generation of mouse models; page unavailable) describe testing C1qa floxed mice with Cx3cr1, Thy1, and Rosa26 CreERT2 lines, and the Results report recombination of a separate tdTomato reporter. Our copy does not address iSuReCre recombination by DCXCreER, P2ry12CreER, or the other lines invoked by the comparison (searched: iSuReCre, DCXCreER, P2ry12CreER, reporter-allele recombination). (LLM, conf=0.76)
Experimental — accuracy not yet measuredMicroglia are the main source of C1q in the brain.
“they are the main source of C1q in the brain (Fonseca et al., 2017)”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Fonseca et al., 2017
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- Authors
- Fonseca, M. I., Chu, S.-H., Hernandez, M. X., Fang, M. J., Modarresi, L., Selvan, P., MacGregor, G. R., & Tenner, A. J.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Tenner, Andrea J.
- Venue
- Journal of Neuroinflammation
- Published
- 2017-03-06
- Volume
- 14
- Issue
- 1
- Pages
- 48-48
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC5340039
- OpenAlex
- W2594676718
- Cited by
- 337
- References
- 63
- Citations by year
- 2026: 26 · 2025: 45 · 2024: 38 · 2023: 53 · 2022: 41 · 2021: 49 · 2020: 30 · 2019: 28 · 2018: 19 · 2017: 8
- FWCI
- 11.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (AG 00538, T32 AG000096)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C1q, complement system, microglia, C1QA, cell-specific gene deletion, Alzheimer's disease, aging, neurodegeneration
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Animals, Newborn, beta-Galactosidase, Brain, Gene Expression Regulation, Luminescent Proteins, Mice, Inbred C57BL, Mice, Transgenic, Neurons, RNA, Messenger, Complement C1q, Microglia, Thy-1 Antigens, Neuropil, Receptors, Chemokine, CD11b Antigen, Mice
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