**Acknowledgements**

In agreement with the effect of Wnt-3a, inhibition of GSK-3β by lithium protects hippocampal neurons from Aβ-induced damage. More importantly, *in vivo* lithium treatment of double transgenic APPswe/PSEN1ΔE9 mice, which is a well characterized *in vivo* model of AD that shows most hallmarks of the disease [140], reduced spatial memory impairment, decreased Aβ oligomers and the activation of astrocytes and microglia [141]. *In vivo*, lithium treatment activated the Wnt signaling as shown by the increase in β-catenin and by the inhibition of GSK-3β [141]. These studies suggest that the loss of normal Wnt/β-catenin signaling activity may be involved in the Aβ-dependent neurodegeneration observed in AD and that the activation of the pathway might have beneficial effects for the treatment of the disease [12]. APPswe/PSEN1ΔE9 mice show decreased levels of adult neurogenesis [142]. In these mice, we evaluated the effect of hypoxia on the generation of new neurons in the hippocampus. As previously mentioned hypoxia induces the activation of the Wnt/β-catenin signaling pathway in the hippocampus of wild-type mice. Mice were exposed to low oxygen and neurogenesis was evaluated by incorporation of BrdU and double staining with DCX. It was determined that hypoxia is a strong stimulator of neurogenesis in AD mice (our unpublished results). Currently we are evaluating whether this effect is related to the activation of the canonical Wnt pathway. Also, we have observed that voluntary wheel running strongly increased neuro‐ genesis in APPswe/PSEN1ΔE9 mice and also decreased Aβ burden and tau phosphorylation (our unpublished results). As previously mentioned, voluntary running was found to increase *de novo* expression of Wnt-3 [101], suggesting that the effects observed in runner AD mice could

In addition to the role of the canonical Wnt signaling, we have studied whether Wnt-5a is able to protect neurons against Aβ oligomers synaptotoxicity [143]. Synaptic failure is an early event in AD, and soluble Aβ oligomers are proposed to be responsible for the synaptic pathology that occurs before the plaque deposition and neuronal death [74, 144]. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic transmission in hippocampal slices dem‐ onstrated that Wnt-5a prevents the decrease in the amplitude of fEPSP and EPSCs induced by Aβ oligomers, indicating that Wnt-5a prevents the synaptic damage triggered by Aβ [143]. Moreover, Wnt-5a prevented the decrease in the postsynaptic density scaffold protein PSD-95 and synaptic loss in cultured hippocampal neurons [143], supporting that Wnt-5a improves

Additionally, the activation of several signaling pathways that crosstalk with the Wnt pathway

As we have discussed throughout this Chapter, the Wnt signaling pathway has fundamental roles in the development and function of the CNS. As discussed, the canonical and noncanonical Wnt signaling cascades have shown to be important for the formation and structure of central synapses, and in addition to the structural effects, Wnt ligands acutely modulate synaptic transmission and plasticity. Also, in the adult brain the Wnt pathway is one of the

also supports the neuroprotective potential of the Wnt cascades in AD [12].

involve the activation of the Wnt signaling pathway.

126 Trends in Cell Signaling Pathways in Neuronal Fate Decision

synaptic function in the presence of Aβ.

**6. Conclusions**

We thank to Felipe G. Serrano for his contribution in the artwork. This work was supported by Grants from FONDECYT (N°1120156) and the Basal Center of Excellence in Science and Technology (CONICYT-PFB12/2007) to NCI and FONDECYT (N°11110012) and Insertion of Postdoctoral Researchers in the Academy (CONICYT-79090027) to LV-N.
