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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 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]
In the citing paper
“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 the citing paper
“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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Metadata
- 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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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