The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation
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Background: Activated microglia are a feature of the host response to neurodegeneration in Parkinson's disease (PD) and are thought to contribute to disease progression. Recent evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of PD and that this may be mediated by a microglial response. Methods: We wished to discover whether the host response to eSNCA would be sufficient to induce significant cytokine production. In vitro cultured BV-2 microglia were used to determine the basic inflammatory response to eSNCA. In vivo , 8-week old Biozzi mice were subjected to a single intranigral injection of either 3 μg SNCA, lipopolysaccharide (LPS) or serum protein (BSA) and allowed to recover for 24 hours. A second cohort of animals were peripherally challenged with LPS (0.5 mg/kg) 6 hours prior to tissue collection. Inflammation was studied by quantitative real-time PCR for a number of pro-inflammatory genes and immunohistochemistry for microglial activation, endothelial activation and cell death. Results: In vitro data showed a robust microglial response to SNCA, including a positive NFĸB response and the production of pro-inflammatory cytokines. Direct injection of SNCA into the substantia nigra resulted in the upregulation of mRNA expression of proinflammatory cytokines, the expression of endothelial markers of inflammation and microglial activation. However, these results were significantly different to those obtained after direct injection of LPS. By contrast, when the animals were injected intracerebrally with SNCA and subsequently challenged with systemic LPS, the level of production of IL-1β in the substantia nigra became comparable to that induced by the direct injection of LPS into the brain. The injection of albumin into the nigra with a peripheral LPS challenge did not provoke the production of a significant inflammatory response. Direct injection of LPS into the substantia nigra also induces cell death in a more robust manner than direct injection of either SNCA or BSA. Conclusion: These results suggest that the presence of eSNCA protein 'primes' microglia, making them susceptible to environmental proinflammatory challenge. For this reason, we hypothesise that where 'inflammation' contributes to the disease progression in PD, it does so in a punctuate manner (on-off) as a result of systemic events.
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Direct injection of LPS into the rodent brain is sufficient to induce neuronal loss.
“Direct injection of LPS into the rodent brain is sufficient to induce neuronal loss [44, 46].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [46]
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- Authors
- Couch, Y., Alvarez-Erviti, L., Sibson, N. R., Wood, M. J., & Anthony, D. C.
- Affiliations
- University of Oxford (GB)
- Churchill Hospital (GB)
- Corresponding author
- Couch, Yvonne
- Sibson, Nicola R
- Wood, Matthew JA
- Anthony, Daniel C
- Venue
- Journal of Neuroinflammation
- Published
- 2011-11-28
- Volume
- 8
- Issue
- 1
- Pages
- 166-166
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3239418
- OpenAlex
- W2064344027
- Semantic Scholar
- 8d36da2a381f6e870ef72f2ae121c4a93eb5d6ac
- Cited by
- 155
- References
- 48
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 8 · 2022: 15 · 2021: 18 · 2020: 13 · 2019: 10 · 2018: 10 · 2017: 15 · 2016: 12 · 2015: 8 · 2014: 15 · 2013: 10 · 2012: 7
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- extracellular alpha-synuclein, Parkinson's disease, microglial activation, neuroinflammation, lipopolysaccharide, substantia nigra, inflammatory cytokines, IL-1β, NF-κB, peripheral inflammation, microglial priming, neuronal cell death, endothelial activation, BV-2 cells, neurodegeneration
- MeSH terms
- Animals, Cell Line, Female, Inflammation, Lipopolysaccharides, Parkinson Disease, Serum Albumin, Substantia Nigra, Tumor Necrosis Factor-alpha, Cytokines, Amyloid beta-Peptides, Cell Death, Microglia, Mice, alpha-Synuclein, Transcription Factor RelA, Interleukin-1beta
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