Alternative complement pathway is activated in the brains of scrapie-infected rodents
Activation of complement system in central nervous system (CNS) of the patients suffering from prion diseases or animal models infected with prion agents experimentally is reported repeatedly, but which pathways are involved in the complement system during prion infection is not well documented. Here, we evaluated the level of complement factor B (CFB), which is the key factor that triggers alterative pathway (AP) of complement in the brain tissues of scrapie-infected mice with various methodologies. We found that the levels of mRNA and protein of CFB significantly increased in the brain tissues of scrapie-infected mice. Morphologically, the increased CFB-specific signal overlapped with the elevated C3 signal in brain sections of scrapie-infected mice, meanwhile overlapped with damaged neurons and activated microglia, but not with the proliferative astrocytes. Additionally, the level of complement factor P (CFP), the key positive regulator of AP, also increased remarkably in the brain tissues of infected mice. The transcriptional levels of CD55 and CD46, two negative regulators of AP, decreased without significance in brain tissues of scrapie-infected mice at the terminal stage. However, the mRNA and protein levels of CFH, another negative regulator of AP, increased. Through the dynamic analyses of the expressions of CFB, CFP, and CFH in brain sections of 139A-infected mice, which were collected at different time-points during incubation period, illustrated time-dependent increase levels of each factor during the incubation period of scrapie infection. Taken together, our data here demonstrate that the AP of complement cascade is activated in the CNS microenvironment during prion infection.
KeywordsComplement Prion CFB CFP CFH
This work was supported by National Natural Science Foundation of China (81772197, 81401670, and 81630062), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018RC330004), National Key R&D Program of China (2018YFC1200305 and 2016YFC1202700), SKLID Development Grant (2015SKLID503 and 2016SKLID603), and the Young Scholar Scientific Research Foundation of China CDC (2016A101).
CC and YL designed the study and drafted the manuscript; CH and RQZ carried out the Western blot; XFX, YM, and LPG carried out the IHC; JLL and QS carried out the IFA; QS carried out the real-time PCR; KX and JW performed the statistical analysis. XPD conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
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Conflict of interest
All the authors declare that they have no conflict of interest.
- 13.Zhang J, Chen L, Zhang BY, Han J, Xiao XL, Tian HY, Li BL, Gao C, Gao JM, Zhou XB, Ma GP, Liu Y, Xu CM, Dong XP (2004) Comparison study on clinical and neuropathological characteristics of hamsters inoculated with scrapie strain 263 K in different challenging pathways. Biomed Environ Sci 17(1):65–78PubMedGoogle Scholar
- 27.Sjoberg AP, Trouw LA, Clark SJ, Sjolander J, Heinegard D, Sim RB, Day AJ, Blom AM (2007) The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 282(15):10894–10900CrossRefGoogle Scholar