We found that non-canonical Wnt5a signaling is up-regulated in mouse brains prior to AD phenotypes and by Ab peptide in cortical neuron cultures. The up-regulated Wnt5a signaling contributes to the inflammation-dependent Ab neurotoxicity in cultures. We also found that Wnt5a up-regulates inflammation regulatory proteins and proinflammatory cytokines and that Wnt5a is required for the Ab-induced proinflammatory cytokines. These observations collectively suggest the following working model : accumulation of Ab in the brain aberrantly up-regulates Wnt5a signaling, which in turn evokes an inflammatory response that causes neurodegeneration or cell death in AD brains. The observed up-regulation of Wnt5a signaling is probably an early etiologically relevant event during AD development. Both Wnt5a and Fz5 proteins significantly increase in the APPswe/ PSEN1DE9 hippocampus at the age of 3.5 months. Previous studies showed that this AD mouse model started to accumulate Ab plaques after 4 months of age and did not develop cognitive impairments until 5–7 months of age. Thus, the observed Wnt5a and Fz5 up-regulation at 3.5 months of age is likely prior to the development of major AD phenotypes. This notion is consistent with the finding that a relatively low concentration of Ab is able to up-regulate Wnt5a and Fz5, suggesting that Wnt5a signaling is a potential target for slowing or blocking early AD BAY-60-7550 pathogenesis. Converging lines of evidence support a critical role of the downregulation of the canonical Wnt/b-catenin pathway in AD pathogenesis. In contrast, the involvement of non-canonical Wnt signaling is less clear. Our findings reveal an early up-regulation of Wnt5a signaling in the hippocampus of 26Tg AD mice. Etiological significance of this dysregulation is suggested by the observation that Wnt5a signaling is necessary for Ab to fully induce neurotoxicity in cortical cultures. Previous studies demonstrated that down-regulation of canonical signaling contributed to Ab neurotoxicity. It is possible that Ab causes parallel up-regulation of the non-canonical Wnt signaling and down-regulation of the canonical signaling to initiate neurotoxicity cascades. The Wnt canonical and non-canonical pathways often antagonize one another. Thus, another possible scenario is that Ab may directly down-regulate the canonical pathway, as suggested by a recent study, which consequently causes the up-regulation of the non-canonical pathway. Our results reveal a neurotoxic activity of Wnt5a signaling, and this Wnt5a activity contributes to Ab toxicity in neuron cultures.