Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation
Open accessAbstract
The aim of this study is to investigate the role and mechanism of microglial NOX2 activation in minimally toxic dose of LPS and Syn-elicited synergistic dopaminergic neurodegeneration. NOX2+/+ and NOX2-/- mice and multiple primary cultures were treated with LPS and/or Syn in vivo and in vitro. Neuronal function and morphology were evaluated by uptake of related neurotransmitter and immunostaining with specific antibody. Levels of superoxide, intracellular reactive oxygen species, mRNA and protein of relevant molecules, and dopamine were detected. LPS and Syn synergistically induce selective and progressive dopaminergic neurodegeneration. Microglia are functionally and morphologically activated, contributing to synergistic dopaminergic neurotoxicity elicited by LPS and Syn. NOX2-/- mice are more resistant to synergistic neurotoxicity than NOX2+/+mice in vivo and in vitro, and NOX2 inhibitor protects against synergistic neurotoxicity through decreasing microglial superoxide production, illustrating a critical role of microglial NOX2. Microglial NOX2 is activated by LPS and Syn as mRNA and protein levels of NOX2 subunits P47and gp91 are enhanced. Molecules relevant to microglial NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-КB P50 as their mRNA and protein levels are elevated after treatment with LPS and Syn. Combination of exogenous and endogenous environmental factors with minimally toxic dose synergistically propagates dopaminergic neurodegeneration through activating microglial NOX2 and relevant signaling molecules, casting a new light for PD pathogenesis.
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Primary midbrain cultures from NOX2 knockout rats are more resistant to neurotoxicity by synergistic treatment with lipopolysaccharide (LPS) and α-synuclein.
“Primary midbrain cultures from NOX2 knockout rats are more resistant to neurotoxicity by synergistic treatment with lipopolysaccharide (LPS) and α-synuclein [84].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [84]
LPS and α-synuclein have a synergistic effect on the upregulation of several key mediators of the inflammatory response, including early activation of PKC, followed quickly by MAPKs and NFκB.
“For example, LPS and α-synuclein have a synergistic effect on the upregulation of several key mediators of the inflammatory response, including early activation of PKC, followed quickly by MAPKs and NFκB [84].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [84]
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References 40 · Cited by 37
Research works printed but not linked: 1
- Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, Faust R, Qian SY, Miller DS, Chignell CF, Wilson B, Jackson-Lewis V, Przedborski S, Joset D, Loike J, Hong JS, Sulzer D, Zecca L. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res. 2011; 19(1): 63– 72. doi: 10.1007/s12640-009-9140-z. Epub 2009 Dec 3. 19957214 PMC3603276 · DOI · Paper page
- Authors
- Zhang, W., Gao, J.-H., Yan, Z.-F., Huang, X.-Y., Guo, P., Sun, L., Liu, Z., Hu, Y., Zuo, L.-J., Yu, S.-Y., Cao, C.-J., Wang, X.-M., & Hong, J.-S.
- Affiliations
- Capital Medical University (CN)
- National Institutes of Health (US)
- Corresponding author
- Zhang, Wei
- Venue
- Molecular Neurobiology
- Published
- 2016-12-15
- Volume
- 55
- Issue
- 1
- Pages
- 619-632
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC6538260
- OpenAlex
- W2566733917
- Cited by
- 37
- References
- 40
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 1
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Natural Science Foundation of China (30770745, 81071015, 81571229)
- the Natural Science Foundation of Beijing, China (7082032)
- Key Project of Beijing Natural Science Foundation, China (kz201610025030, ,4161004, kz200910025001)
- the National Key Basic Research Program of China (2011CB504100)
- National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2013BAI09B03)
- The project of Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084)
- High Level Technical Personnel Training Project of Beijing Health System, China (2009-3-26)
- The Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (IDHT20140514)
- Capital Clinical Characteristic Application Research (Z121107001012161)
- the Beijing Healthcare Research Project, China (JING-15-2, JING-15-3)
- Excellent Personnel Training Project of Beijing, China (20071D0300400076)
- Key Project of National Natural Science Foundation of China (81030062)
- Basic-Clinical Research Cooperation Funding of Capital Medical University (2015-JL-PT-X04, 10JL49, 14JL15)
- Youth Research Fund, Beijing Tiantan Hospital, Capital Medical University, China (2014-YQN-YS-18, 2015-YQN-15, 2015-YQN-05, 2015-YQN-14, 2015-YQN-17)
- 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
- lipopolysaccharide, alpha-synuclein oligomers, dopaminergic neuron loss, NADPH oxidase, Parkinson's disease, synergistic neurotoxicity, superoxide, reactive oxygen species, microglial activation, MAPK signaling, NF-κB, dopaminergic neurons
- MeSH terms
- Neuroprotection, NADPH Oxidase 2, Animals, Cell Membrane, Enzyme Activation, Lipopolysaccharides, Mice, Inbred C57BL, Nerve Degeneration, Neurotoxins, Signal Transduction, Rats, Sprague-Dawley, Microglia, Protein Subunits, alpha-Synuclein, Dopaminergic Neurons
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