Year: 2018
Type: article
Abstract: Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer’s, Parkinson’s or prion diseases. In prion diseases, space and time correlations between deposition of disease-associated, pathogenic form of the prion protein or PrPScand microglial-mediated neuroinflammation has been established. Yet, it remains unclear whether activation of microglia is triggered directly by a contact with PrPSc, and what molecular features of PrPScmicroglia sense and respond to that drive microglia to inflammatory states. The current study asked the questions whether PrPSccan directly trigger activation of microglia and whether the degree of microglia response depends on the nature of terminal carbohydrate groups on the surface of PrPScparticles. PrPScwas purified from brains of mice infected with mouse-adapted prion strain 22L or neuroblastoma N2a cells stably infected with 22L. BV2 microglial cells or primary microglia were cultured in the presence of purified 22L. We found that exposure of BV2 cells or primary microglia to purified PrPSctriggered proinflammatory responses characterized by an increase in the levels of TNFα, IL6, nitric oxide (NO) and expression of inducible Nitric Oxide Synthase (iNOS). Very similar patterns of inflammatory response were induced by PrPScpurified from mouse brains and neuroblastoma cells arguing that microglia response is independent of the source of PrPSc. To test whether the microglial response is mediated by carbohydrate epitopes on PrPScsurface, the levels of sialylation of PrPScN-linked glycans was altered by treatment of purified PrPScwith neuraminidase. Partial cleavage of sialic acid residues was found to boost the inflammatory response of microglia to PrPSc. Moreover, transient degradation of Iκβα observed upon treatment with partially desialylated PrPScsuggests that canonical NFκB activation pathway is involved in inflammatory response. The current study is the first to demonstrate that PrPSccan directly trigger inflammatory response in microglia. In addition, this work provides direct evidence that the chemical nature of the carbohydrate groups on PrPScsurface is important for microglial activation.
Source: Scientific Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W2883337393