The Study On The Activation Of The Complement System In The Brains Of Scrapie-infected Rodents

Prion diseases (PrDs), also designated as transmissible spongiform encephalopathies (TSEs), are a group of chronic (long incubation period) and fatal (fatal rate 100%) neurodegenerative disorders that affect both humans and many other mammalian animals. Human PrDs are classified as Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), and animal PrDs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease in mule deer and elk and so on. The infectious agent is prion. All prion diseases share common neuropathological features in the central nervous system (CNS), including spongiform vacuolation, amyloid plaque deposition, neuronal loss and astrocytosis.The complement system, which consists of at least 30 sorts of soluble and membrane-bound active components, is the first line of defense against pathogenic infection. The complement cascade acts as an intricate immune surveillance system, primarily participating in the opsonization of invading pathogens, recruitment of inflammatory cells, lysis of infected cells, and disposal of immune complex and apoptotic cells, and in this way, it sets up a linkage between the innate and the adaptive immunity. As an integral part of the innate immune system, the complement system has been reported to involve in the pathogenesis of PrDs. However, the states of the expressions and activities of complement proteins during prion 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 Clq 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 PrDs.