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Remarkable Activation of the Complement System and Aberrant Neuronal Localization of the Membrane Attack Complex in the Brain Tissues of Scrapie-Infected Rodents

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Abstract

As an integral part of the innate immunity, the complement system has been reported to involve in the pathogenesis of prion diseases (PrD). However, the states of expression and activity of complement proteins in experimental models of scrapie infection are still not fully understood. Herein, the state of complement activation, the presence, and distribution as well as localization of C3 and membrane attack complex (MAC) in the brains of several scrapie-infected rodents were comparatively assessed through various methodologies. Our data illustrated a significant increase in the total complement activity (CH50, U/ml) in several scrapie-infected rodent brains at the terminal stage and a time-dependent upregulation of C1q in 263K-infected hamsters during the incubation period, intimating the sustained and progressive activation of the classical pathway during PrD progression. Confocal microscopy revealed robust activation of C3 and its localization to various central nervous system (CNS) cells with differential morphology in the brain tissues of both 263K-infected hamsters and 139A-infected C57BL/6 mice at disease end stages. Dynamic analyses of MAC in the brains of 263K-infected hamsters and 139A-infected C57BL/6 mice demonstrated remarkably time-dependent deposition during the incubation period, which may highlight a persistently activated terminal complement components. Moreover, immunofluorescent assays (IFAs) showed that MAC-specific signals appeared to overlap with morphologically abnormal neurons rather than proliferative astrocytes or activated microglia throughout the CNS of both 263K-infected hamsters and 139A-infected C57BL/6 mice. Overall, these results indicate that the activation of the complement system and the subsequent localization of the complement components to neurons may be a hallmark during prion infection, which ultimately contribute to the neurodegeneration in PrD.

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Acknowledgments

This work was supported by Chinese National Natural Science Foundation Grants (81301429, 81401670), China Mega-Project for Infectious Disease (2011ZX10004-101, 2012ZX10004215), SKLID Development Grant (2012SKLID102, 2011SKLID211).

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Authors and Affiliations

  1. State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing, 102206, China

    Yan Lv, Cao Chen, Bao-Yun Zhang, Kang Xiao, Jing Wang, Li-Na Chen, Jing Sun, Chen Gao, Qi Shi & Xiao-Ping Dong

  2. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310003, China

    Yan Lv, Cao Chen, Jing Wang, Chen Gao, Qi Shi & Xiao-Ping Dong

  3. Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

    Xiao-Ping Dong

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  1. Yan Lv
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  2. Cao Chen
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Correspondence to Xiao-Ping Dong.

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Yan Lv and Cao Chen contributed equally to this study.

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Supplemental Figure 1

Serially optical scanning of the individual graphs of C5b-9, NeuN, DAPI and merged ones in the brain slices (cortex region) per 1.0 μm by confocal microscopy. A. 263K-infected hamster (×100). B. normal hamster (×100). C. 139A-infected mouse (×100). D. normal mouse (×100). Arrow points out that the images are captured from the bottom to the top. (PDF 973 kb)

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Lv, Y., Chen, C., Zhang, BY. et al. Remarkable Activation of the Complement System and Aberrant Neuronal Localization of the Membrane Attack Complex in the Brain Tissues of Scrapie-Infected Rodents. Mol Neurobiol 52, 1165–1179 (2015). https://doi.org/10.1007/s12035-014-8915-2

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  • DOI: https://doi.org/10.1007/s12035-014-8915-2

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