Their results indicate a synapto-protective activity of Wnt5a signaling soon after Ab exposure. Because Ab-up-regulated Wnt5a does not occur by 1 hour after Ab treatment in cultures and 500 nM Ab itself does not induce obvious cell death in this period, we reason that basal Wnt5a has a synaptoprotective activity. On the other hand, sustained up-regulation of Wnt5a, which occurs at 2 hours after Ab treatment, probably potentiates neurotoxicity. We further found that activation of Wnt5a signaling stimulates the expression of proinflmmatory cytokine in cortical cultures. This finding indicates that up-regulation of Wnt5a may mediate Ab-induced neuroinflammation in AD brains. Because the Ab-elicited inflammatory response and alleviated Ab-induced neurotoxicity was impaired by the anti-Wnt5a antibody and Box5, Ab likely induces Wnt5a secretion, although the kinetics of the secretion is currently unknown. In peripheral non-neuronal systems, Wnt5a is implicated in inflammation of multiple chronic disorders, including rheumatoid arthritis, sepsis, atherosclerosis, melanoma, and psoriasis. Our results provide the initial evidence for a critical role of Wnt5a signaling in the regulation of inflammatory responses in CNS disorders. Because the primary cortical cultures used in this study contain neurons and glia, we currently do not know the specific type of glial cells through which Wnt5a evokes the observed inflammatory responses. In a recent study, Halleskog et al. reported that Wnt3a stimulated the expression of proinflammatory cytokines in microglia. It would be interesting to know if Wnt5a regulates neuroinflammation by stimulating the same or different types of glia. Nonetheless, the findings on Wnt5a and Wnt3a indicate that proteins in the Wnt family may orchestrate neuroinflammatory response during AD pathogenesis. Microorganisms are the most abundant and diverse forms of life and are essential in the functioning of all ecosystems. However, despite their importance and ubiquity, only a tiny fraction of them is well understood due to their failure to grow under standard laboratory culture conditions. With this limitation, less than 1% of the total number of microbial species have been isolated in pure cultures. Our knowledge of microbial biodiversity is thus severely impaired by relying solely on cultivated microorganisms, leading to a limited appreciation of functional diversity. Recently the development of Nilotinib metagenomic approaches has opened the window on the richness of uncultured biodiversity.