Neurodegeneration by Activation of the Microglial Complement-Phagosome Pathway
Open accessAbstract
Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four consecutive days with bacterial LPS maintained an elevated microglial inflammatory phenotype and induced loss of dopaminergic neurons in the substantia nigra. The same total cumulative LPS dose given within a single application did not induce neurodegeneration. Whole-genome transcriptome analysis of the brain demonstrated that repeated systemic LPS application induced an activation pattern involving the classical complement system and its associated phagosome pathway. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3-deficient mice, confirming the involvement of the complement system in neurodegeneration. Our data demonstrate that a phagosomal inflammatory response of microglia is leading to complement-mediated loss of dopaminergic neurons.
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The in vivo model based on intraperitoneal injection of LPS induces a well-defined microglial proinflammatory phenotype that is different from the molecular signature of disease-associated microglia.
“It has been demonstrated that this in vivo model induces a well-defined microglial proinflammatory phenotype different to the recently characterized molecular signature of disease-associated microglia (Bodea et al., 2014; Krasemann et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Bodea et al., 2014
The Introduction and the section on microglial activation after systemic LPS application (page unavailable) report an inflammatory microglial response to intraperitoneal LPS in mice. The cited paper does not compare that response with the molecular signature of disease-associated microglia, so it supports only the first part of the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglial TET2 is upregulated in vivo in two well-defined models of microglia polarization: a neuroinflammatory mouse model induced by repeated intraperitoneal injections of LPS, and AD, including human patients and transgenic mice (5xFAD).
“We also found that microglial TET2 is upregulated in vivo in two-well defined models of microglia polarization; in a neuroinflammatory mouse model induced by repeated intraperitoneal injections of LPS (Krasemann et al., 2017; Bodea et al., 2014), and in AD, including human patients and transgenic mice (5xFAD).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Bodea et al., 2014
Peripheral endotoxin can activate the classical complement system in the brain, resulting in neuronal loss that can be prevented in complement C3-deficient mice.
“Peripheral endotoxin can activate the classical complement system in the brain, resulting in neuronal loss that can be prevented in complement C3-deficient mice [63].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [63]
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References 47 · Cited by 234
- Authors
- Bodea, L.-G., Wang, Y., Linnartz-Gerlach, B., Kopatz, J., Sinkkonen, L., Musgrove, R., Kaoma, T., Muller, A., Vallar, L., Di Monte, D. A., Balling, R., & Neumann, H.
- Affiliations
- University of Bonn (DE)
- University of Luxembourg (LU)
- German Center for Neurodegenerative Diseases (DE)
- Centre de Recherche Public de la Santé (LU)
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-06-18
- Volume
- 34
- Issue
- 25
- Pages
- 8546-8556
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6608212
- OpenAlex
- W1987735399
- Cited by
- 234
- References
- 47
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 34 · 2023: 23 · 2022: 17 · 2021: 34 · 2020: 26 · 2019: 22 · 2018: 20 · 2017: 18 · 2016: 14 · 2015: 11 · 2014: 1
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KFO177, EXC 1023, SFB 704, FOR1336)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- neurodegeneration, microglial activation, complement system, phagosome pathway, lipopolysaccharide, systemic inflammation, dopaminergic neurons, substantia nigra, complement C3, Parkinson's disease, neuroinflammation
- MeSH terms
- Animals, Complement System Proteins, Complement Activation, Complement C3, Male, Mice, Inbred C57BL, Nerve Degeneration, Neural Pathways, Phagosomes, Microglia, Mice, Knockout, Mice, Mice, 129 Strain, Dopaminergic Neurons
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