Differential Response Of Microglia To Distinct Alpha-Synuclein Assemblies A. Van der Perren1, G. Gelders1, L. Bousset2, J. Peralta Ramos3, W. Peelaerts1, C. Van den Haute1, R. Melki2, Veerle Baekelandt1 1Lab. for Neurobiology and Gene Therapy, KU Leuven, Belgium, 2Lab. d'Enzymologie et
Biochimie Structurales, CNRS, France,3Centro de Investigaciones en Bioquímica Clínica e Inmunología, University of Córdoba, Argentina. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. There is emerging evidence that these protein aggregates can adopt distinct conformations characterized by noticeable differences in phenotypic features. The discovery of the prion-like transmissible nature of these proteins suggests a pathogenic trigger which propagate throughout the nervous system underlying the progression of the disease. In addition, there is mounting evidence that neuroinflammatory processes are closely linked to neurodegeneration during ageing. In the present study, we investigated the immunological properties of different α-synuclein (α-SYN) assemblies to define the role of the innate immune system in Parkinson's disease. We examined the microglia cell response to different recombinant α-SYN assemblies via exogenous addition to primary microglia cultures. We studied uptake and degradation of the different α-SYN assemblies in our primary microglia cultures and analyzed the microglial status using qPCR. We showed that distinct fibrillar α-SYN assemblies promote a pro-inflammatory activation of microglia, however differences between fibrillar assemblies could be observed. Oligomeric species, thought to be the primary species responsible for the disease, were unable to trigger the same cascades. Next, we assessed the innate immune response towards α-SYN in vivo by intranigral injection of different recombinant α-SYN assemblies. We observed an increased microglia activation in animals injected with fibrillar α-SYN. These results support our hypothesis that specific α-SYN assemblies drive the pro-inflammatory activity of microglia. Further, we intravenously injected different fibrillar assemblies into the mouse tail vein and observed α-SYN spreading toward the brain accompanied with a remarkable monocyte infiltration. Currently we are assessing different patient-derived in vitro amplified α-SYN assemblies in terms of neurotoxicity and immunogenicity in vivo. Immune alterations in response to α-SYN may play a critical role in modulating Parkinson's disease progression.
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