title: Abnormal activation of microglia accompanied with disrupted CX3CR1/CX3CL1 pathway in the brains of the hamsters infected with scrapie agent 263K.
abstract: Microglial cells are resident mononuclear phagocytes of the central nervous system (CNS). Active proliferation of microglia in the brain has been identified in neurodegenerative disorders, including some kinds of prion disease. However, the detailed regional distribution between microglia and PrP(Sc) deposition has not been presented, and investigation of fractalkine signaling which is involved in the regulation of activation of microglia in prion disease is not well documented. In this study, the disease phenomenon of microglial accumulation in the CNS was thoroughly analyzed using a scrapie-infected experimental model. Western blots of microglia-specific markers Iba1 and CD68, immunohistochemical and immunofluorescent assays demonstrated obviously activation of microglia in almost whole brain regions in the infected animals. Under the dynamic analysis on hallmarks of activation of microglia, a time-dependent increase of Iba1 and CD68 was detected, accompanied by accumulation of PrP(Sc) and progression of neurodegenerative symptoms. With serial brain sections and double staining of Iba1 and PrP(Sc), we observed that the microglia distributed around PrP(Sc) deposits in 263K-infected hamsters' brains, proposing PrP(Sc) phagocytosis. Flow cytometry assays with the single-cell suspensions prepared from the cortical region of the infected brains verified an activation of microglial population. ELISA assays of the cytokines in brain homogenates revealed significant upregulations of interleukin (IL)-1β, IL-6 and TNF-α when infected. Evaluation of fractalkine signaling in the infected hamsters' brains showed progressively downregulation of CX3CL1 during the incubation. Prion peptide PrP106-126 also disrupted fractalkine and evoked microglial activation in rat primary neuron-glia mixed cultures. Our data here demonstrate an activated status of microglia in CNS tissues of infectious prion disease, possibly through fractalkine signaling deficiency.
authors.affiliation: School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
authors.forename: Wu-Ling
authors.initials: WL
authors.lastname: Xie
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Bao-Yun
authors.initials: BY
authors.lastname: Zhang
authors.forename: Han-Shi
authors.initials: HS
authors.lastname: Gong
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Shao-Bin
authors.initials: SB
authors.lastname: Wang
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Cao
authors.initials: C
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Dong
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D018620:PrPSc Proteins / Q000472:pathogenicity*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012608:Scrapie / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D054428:Chemokine CX3CL1; D053583:Interleukin-1beta; D015850:Interleukin-6; D018620:PrPSc Proteins; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha