No increase of phosphorylation at either Thr181 or Thr205 was detected in the transgenic flies. These differences in the findings of previous studies could be due either to differences in species, cell sources, or other experimental conditions such as the levels of expression of LRRK2 and tau. LRRK2 has been reported to phosphorylate TAOK3, a kinase with high sequence homology to MARK kinase, suggesting a possibility of LRRK2-mediated indirect phosphorylation of tau. The present results indicating that LRRK2-mediated phosphorylation of tau enhances its Echinatin dissociation from tubulin suggest that this process is one of the important regulatory mechanisms for microtubule disassembly, which may lead to reduced neurite outgrowth. In mouse neurons, however, there has been some controversy as to whether kinase activity of LRRK2 reduces or promotes neurite outgrowth. Neurite length and branching are reportedly increased by LRRK2-knockdown or LRRK2-kinase inactivation, whereas another study has found a decrease of neurons differentiated from LRRK2-knockout mouse embryonic stem cells. Furthermore, kinase active mutant G2019SLRRK2 expression in neurons has been reported to markedly reduced neurite length in comparison with the wild-type and or kinase-dead mutant.These results suggest that CD36 blockade did not downregulate TNF-a mRNA transcription to the extent that would affect its protein synthesis and support a central role of CD36 in the signaling that leads to the up-regulation of IL-6, IL1b in microglia upon exposure to PrP106–126. It is well established that stressful conditions can trigger the expression of iNOS, which can generate NO from Larginine. In this study, we reported that PrP106–126 induced an increase in iNOS level and NO secretion in primary microglia. This is in line with other reports that almost invariably reported the upregulation of iNOS and release of NO in macrophages and microglia exposed to neurotoxic prion peptides. Moreover, we showed that CD36 blockade significantly abrogated the effect of Licochalcone-A PrP106–126 treatment on iNOS expression and NO production. These results are consistent with previous reports showing that CD36 mediates free radical production in many neuroinflammatory conditions including Alzheimer disease and cerebral ischemia, and support a key role of CD36 in prion diseases-associated oxidative stress by triggering iNOS upregulation and NO production. Several lines of evidence indicate that NF-kB activation is crtitical for the induction of iNOS and the upregulation of inflammatory cytokines such as IL-1b and IL-6. Moreover, the activation of NF-kB in macrophages and microglia exposed to neurotoxic prion peptides is well documented. NF-kB activation was also linked to CD36 signaling. We therefore examined the effect of CD36 blocking on PrP106–126-induced NF-kB activation. The observed results showed nuclear translocation of p65 in PrP106–126-treated cells even in the case of anti-CD36 monoclonal antibody pretreatment. This finding may account for why the release of TNF-a in the treated cells was not affected by CD36 blockade. However, keeping in mind that a wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-kB, this result is not conclusive and does not rule out the possibilty that CD36 blockade may inhibit microglial activation by interfering with NF-kB activation. We can speculate, for example, that PrP106–126 leads to the activation of NF-kB through several pathways and that, if any, only one or some of these pathways are CD36-mediated. We also examined the effect PrP106–126 treatment on caspase-1 activation.