CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease

Shi Zhang,Jing Pan,Jian-Qing Ding,Sheng-Di Chen,Guo-Qiang Lu,Li-Peng Tian,Ying-Jie Zhang,Xi-Jin Wang

doi:10.1186/1742-2094-8-154

Abstract

BackgroundIncreasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinson's disease (PD). CD200-CD200R signalling has been shown to be critical for restraining microglial activation. We have previously shown that expression of CD200R in monocyte-derived macrophages, induced by various stimuli, is impaired in PD patients, implying an intrinsic abnormality of CD200-CD200R signalling in PD brain. Thus, further in vivo evidence is needed to elucidate the role of malfunction of CD200-CD200R signalling in the pathogenesis of PD.Methods6-hydroxydopamine (6-OHDA)-lesioned rats were used as an animal model of PD. CD200R-blocking antibody (BAb) was injected into striatum to block the engagement of CD200 and CD200R. The animals were divided into three groups, which were treated with 6-OHDA/Veh (PBS), 6-OHDA/CAb (isotype control antibody) or 6-OHDA/BAb, respectively. Rotational tests and immunohistochemistry were employed to evaluate motor deficits and dopaminergic neurodegeneration in animals from each group. HPLC analysis was used to measure monoamine levels in striatum. Morphological analysis and quantification of CD11b- (or MHC II-) immunoreactive cells were performed to investigate microglial activation and possible neuroinflammation in the substantia nigra (SN). Finally, ELISA was employed to assay protein levels of proinflammatory cytokines.ResultsCompared with 6-OHDA/CAb or 6-OHDA/Veh groups, rats treated with 6-OHDA/BAb showed a significant increase in counts of contralateral rotation and a significant decrease in TH-immunoreactive (TH-ir) neurons in SN. A marked decrease in monoamine levels was also detected in 6-OHDA/BAb-treated rats, in comparison to 6-OHDA/Veh-treated ones. Furthermore, remarkably increased activation of microglia as well as up-regulation of proinflammatory cytokines was found concomitant with dopaminergic neurodegeneration in 6-OHDA/BAb-treated rats.ConclusionsThis study shows that deficits in the CD200-CD200R system exacerbate microglial activation and dopaminergic neurodegeneration in a 6-OHDA-induced rat model of PD. Our results suggest that dysfunction of CD200-CD200R signalling may be involved in the aetiopathogenesis of PD.

Highlights

Increasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinson’s disease (PD)
To investigate the role of CD200-CD200R dysfunction in 6-OHDAinduced neurotoxicity, we employed a CD200R monoclonal antibody to block CD200-CD200R engagement, which was first used by Wright, G
Luo et al [40] examined CD200R expression and regulation in monocyte-derived macrophages (MDMs), the peripheral counterpart of microglia, in PD patients and in old and young healthy controls. They found that basal CD200R expression is similar in MDMs from young control, old control and PD patients; expression of CD200R in MDMs induced by various stimuli is impaired in the older groups, especially in PD patients, implying an intrinsic abnormality of CD200-CD200R signalling in PD brain

Summary

Introduction

Increasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinson’s disease (PD). Emerging investigations suggest that multiple factors, both genetic and acquired, contribute to the loss of dopaminergic cells in the substantia nigra (SN) of these patients [2,3,4] Among these culprits, accumulated evidence suggests that neuroinflammation, which is characterised by activation of microglia and subsequent production of proinflammatory cytokines, may play an important role in the neurodegenerative process in PD. Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14,15,16,17,18,19,20,21,22] Taken together, those previous studies suggest that persistent activation of microglia is dynamically involved in the disease’s progression

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