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

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.

Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt‐Jakob disease

“…APOE mRNA and C1q are only slightly elevated at clinical stages in FU‐CJD infected mouse brain, and thus their higher 4.3‐ and 6.6‐fold protein increases here indicate their accumulation in concert with pathologic PrP‐res formation. C1q protein levels in TSE infected whole brain can be ∼10‐fold normal in contrast to weak mRNA elevations. A substantial elevation of C1q is also found in AD amyloid neurodegeneration, and as an innate immune response to invading microorganisms.…”

Loss of region-specific glial homeostatic signature in prion diseases

“…Fcgr2b is involved in natural killer cell mediated neurotoxicity, and was previously shown to be upregulated in ME7- and RML-infected mice [27, 31]. C1qa, C1qb and C1qc , the subcomponents of the complement cascade factor C1q , and C4a component of the complement cascade were found to be upregulated in 22L-, RML-, ME7- and 301V-infected mice and 263K-infected hamsters [27, 31, 50, 51]. In periphery, PrP Sc interaction with C1q is required for sequestration of prions by spleen and infection of follicular dendritic cells [52].…”

Microglia in prion diseases

“…We have long held the view that complement facilitates prion pathogenesis by trapping and retaining prions in secondary lymphoid organs after peripheral infection (58,59). The complement cascade was reported to be activated in the brains of patients with Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease, as well as in animal models of prion infection (60)(61)(62). Overall, complement activity was upregulated in several prion-infected rodent brains in a timedependent manner, and complement components such as C1q, C3, and membrane attack complex (MAC) were also upregulated and detected in various cell types, including microglia (62).…”

“…The complement cascade was reported to be activated in the brains of patients with Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease, as well as in animal models of prion infection (60)(61)(62). Overall, complement activity was upregulated in several prion-infected rodent brains in a timedependent manner, and complement components such as C1q, C3, and membrane attack complex (MAC) were also upregulated and detected in various cell types, including microglia (62). Nevertheless, the contribution of the complement system in prion-induced neurodegeneration in the CNS seems to be minor, as mice deficient in various complement components developed disease similarly to WT mice upon intracerebral challenge with prions (58,59,63).…”