The result showed that PrP106–126 stimulated capase-1 cleavage and that CD36 blockade did not interfere with this activation although a slight reduction of caspase-1 cleavage was observed after a moderate PrP106–126 treatment. This suggests that CD36 may not play a central role in PrP106–126-induced capase-1 activation. Caspase-1 is an inflammatory caspase, whose main substrates are cytokines that are crucial to the inflammatory response such IL-1b and IL-18. Caspase-1 is present as an inactive proform in the cytoplasm and it is activated by proteolytic selfprocessing. Several multimolecular proteins complexes, referred to as inflammasomes, have been identified as caspase-1 activators. To our knowledge, this is the first time an association between neurotoxic prion peptides and activation of caspase-1 in microglia is reported. This finding suggests that inflammsome activation may be involved in neurotoxic prion peptides-induced inflammation and, if confirmed by further studies, would add prion diseases to a long list of diseases and inflammatory conditions that have been associated with inflammasome. Caspase-1 activation leads to post-translational processing and release of the mature,Deltaline biologically active forms of IL-1b and IL-18, which are potent mediators of inflammation, being responsible for a variety of effects associated with host responses to microbial invasion and tissue damage. As mentioned above, PrP106–126 induced IL-1b upregulation and capase-1 activation. However, CD36 blockade resulted only in the inhibition of PrP106–126induced upregulation of IL-1b without a significant effect on capase-1 activation, which suggests that CD36 mediates PrP106– 126-induced upregulation of IL-1b through a capase-1-independent pathway. Accordingly, the fact that CD36 blockade significantly downregulated mRNA expression of IL-1b in PrP106–126-treated cells supports a direct involvement of CD36mediated signaling at the level of mRNA transcription of IL-1b in microglia exposed to neurotoxic prion peptides. Finally, we examined the effect of PrP106–126 treatment on Fyn phosphorylation. Fyn is a membrane associated non-receptor protein tyrosine kinase that belongs to the Src family of cytoplasmic tyrosine kinase. Fyn is expressed predominately in tissues of neuronal and hematopoietic origin and has been shown to be involved in CD36-mediated signaling. The decrease in p-Fyn level observed after CD36 blockade in PrP106– 126 treated microglia suggests that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. This is supported by Talatisamine preliminary results from a research work in our lab on CD36 signaling during PrP106–126induced micrglial activation, which is currently underway, and which showed that Src tyrosine kinase inhibitor, PP2, can significantly downregulate PrP106–126-induced i-NOS upregulation in BV2 micrglia. In conclusion, we have shown that CD36 is involved in PrP106– 126-induced microglial activation and that neurotoxic prion peptides can induce caspase-1 activation in microglia. These findings unveil a previously unrecognized role of CD36 as a surface molecule involved in neurotoxic prion peptides-microglia interactions and raise the possibility of inflammasome involvement in the pathogenesis of prion diseases, thus providing new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides. Although more studies are needed to confirm and explore these initial findings, our study identified a potential molecular target for the treatment of prion diseases and provides perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling. The earliest stages of the disease show accumulation of abnormal tau in the entorhinal cortex whereas later stages show accumulation in the hippocampus followed by neocortical areas.