Modulation of microglal inflammatory response to alpha-synuclein oligomers by heparin-induced GAPDH prefibrils

SEPULVEDA-DIAZ J; SOCÍAS, B; TORRES BUGEAU, C.; PAPY-GARCIA D,; MICHEL P; CHEHÍN ROSANA; RAISMAN-VOZARI R,

Chicago

Congreso; Neurosciences 2015. 45th Annual Society for Neuroscience Meeting; 2015

677. Alpha-Synuclein Mechanisms in Parkinson´s DiseaseLocation: Hall ATime: Wednesday, October 21, 2015, 8:00 AM - 12:00 PMProgram#/Poster#: 677.05/D40Topic: C.03. Parkinson?s DiseaseTitle: Modulation of the microglial inflammatory response to alpha-synuclein oligomers by heparin-induced GAPDH prefibrilsAuthors: *J. E. SEPULVEDA DIAZ1, S. B. SOCIAS2,1, C. AVILA2, C. M. TORRES- BUGEAU2, D. PAPY-GARCIA3, P. P. MICHEL1, R. N. CHEHIN2, R. RAISMAN-VOZARI1;1ICM-INSERM U1127, Hop. Pitie-Salpetriere, Paris, France; 2Inst. Superior de Investigaciones Biológicas (INSIBIO),CONICET-UNT, Tucumán, Argentina; 3CRRET ERL CNRS 9215, UPEC, Créteil, FranceAbstract: In Parkinson?s disease (PD) brain, the protein alpha-synuclein (alpha-syn) accumulates to form intra- and extracellular amyloid aggregates called Lewy bodies (LB) and Lewy neurites. The aggregation process occurs progressively through the production of intermediary (e.g., oligomeric) species that form mature and insoluble fibrillary structures. Two sort of arguments suggest that he multifunctional enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) may intervene in the aggregation process: (i) GAPDH colocalizes with α-syn in amyloid deposits from PD brains and (ii) it also promotes the formation of LB-like aggregates in cell culture models. Still consistent with this view, we have shown previously that heparin-induced GAPDH prefibrillar species (HI-GAPDHpf) strongly modify alpha-syn aggregation kinetics and reduce the neurotoxicity of alpha-syn species by accelerating the conversion of toxic oligomers (alpha-syn-oli) into less toxic fibrils (Avila et al, J Biol Chem, 2014). In the present work, we aimed to evaluate the ability of HI-GAPDHpf to modulate brain inflammatory processes in response to alpha-syn-oli (samples prepared according to procedures described by Avila et al, 2014) through the use of a model system of microglial cells in culture. Microglial cells activated by alpha-syn-oli (500 nM; 24h) displayed a hypertrophic morphology and showed increased expression of the ionized calcium-binding adapter molecule 1. Moreover, alpha-syn-oli treatment led to increased production and release of two pro-inflammatory cytokines (TNF-alpha and IL-1beta) and to enhanced generation of intracellular radical oxygen species. We will describe how inflammatory processes are modulated by HI-GAPDHpf in alpha- syn-oli-activated microglial cells.