Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK
Abstract
CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.
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In the absence of CD200-CD200R interaction, microglia become reactive and excessively proliferative.
“in the absence of this interaction, microglia become reactive and excessively proliferative”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [32]
The binding of neuronal CD200 to its microglial receptor CD200R is necessary for restricting microglial activation in disease models including rotenone neurotoxicity and Toxoplasma encephalitis.
“the binding of neuronal CD200 to its microglial receptor CD200R is necessary for restricting microglial activation in disease models including rotenone neurotoxicity [32] and Toxoplasma encephalitis [33]”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [32]
In rat PD models, deficiency of CX3CL1 or CX3CR1 and dysfunction of CD200-CD200R signaling increase microglial activation and degeneration of DA neurons.
“In rat PD models, both deficiency CX3CL1 or CX3CR1 as well as the dysfunction of CD200-CD200R signaling have been shown to increase microglial activation and the degeneration of DA neurons (Wang et al., 2011; Zhang et al., 2011).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Wang et al., 2011
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- Authors
- Wang, X.-J., Zhang, S., Yan, Z.-Q., Zhao, Y.-X., Zhou, H.-Y., Wang, Y., Lu, G.-Q., & Zhang, J.-D.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Jiao Tong University (CN)
- University of Nebraska Medical Center (US)
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 50
- Issue
- 9
- Pages
- 1094-1106
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2078755005
- Cited by
- 108
- References
- 62
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 16 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 5 · 2012: 11
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- 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
- Parkinson's disease, dopaminergic neuron loss, substantia nigra, rotenone, iron neurotoxicity, NADPH oxidase, superoxide, p38 MAPK, aging, ICAM-1, MHC class II, microglial activation
- MeSH terms
- Aging, Animals, Cells, Cultured, Dopamine, Iron, Mesencephalon, Neurons, Parkinson Disease, Receptors, Immunologic, Rotenone, Superoxides, Antigens, CD, Gene Expression, Polymerase Chain Reaction, Rats, Sprague-Dawley, Microglia, Intercellular Adhesion Molecule-1, Cell Culture Techniques, Antibodies, Blocking, NADPH Oxidases, p38 Mitogen-Activated Protein Kinases, Rats
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