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 (Fig. 3), suggesting that Wnt5a signaling is a potential target for slowing or blocking early AD pathogenesis. Converging lines of evidence support a critical role of the down- regulation 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 demon- strated that down-regulation of canonical signaling contributed to Ab neurotoxicity [27,30,34,62]. 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 [63]. Thus, another possible scenario is that Ab may directly down-regulate the canonical pathway, as suggested by a recent study [33], 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. Cerpa et al. recently reported that acute administration of exogenous Wnt5a (500 nM) prevented Ab-induced synaptotoxi- city within 40 min after Ab oligomer application [36]. 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 (Fig. 3H) and 500 nM Ab itself does not induce obvious cell death in this period (Fig. 4A and S1), we reason that basal Wnt5a has a synapto- protective activity. On the other hand, sustained up-regulation of Wnt5a, which occurs at 2 hours after Ab treatment (Fig. 3H), probably potentiates neurotoxicity. We further found that activation of Wnt5a signaling stimulates the expression of proinflmmatory cytokine in cortical cultures References 1. Hardy J, Selkoe DJ (2002) The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science 297: 353–356. 2. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-[beta] in Alzheimer’s disease. Nat Rev Neurosci 8: 499. 3. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, et al. (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21: 383–421. 4. 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