ChileAlzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid b-peptide (Ab). We report here molecular changes induced by Ab, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Ab fibrils, as an in vivo model of the disease. Results indicate that in both systems, Ab neurotoxicity resulted in the destabilization of endogenous levels of b-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3b promoted the survival of post-mitotic neurons against Ab neurotoxicity and recovered cytosolic b-catenin to control levels. Moreover, the neurotoxic effect of Ab fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Ab fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing b-catenin levels and improved the deficit in spatial learning induced by Ab. Our results are consistent with the idea that Ab-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.

Current evidence supports the notion that b-amyloid deposits or Ab intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid b-sheet breaker peptide (iAb5p) on the rat behavioral deficit induced by the intrahippocampal Ab-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAb5p treatment, hippocampaldependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Ab deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with b-sheet breaker peptides may be used as a potential therapy for AD patients. Molecular Psychiatry (2004) 9, 953-961.

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The activation of the canonical Wnt signaling pathway protects hippocampal neurons against the toxicity of Alzheimer's amyloid-beta-peptide (Abeta), however, the role played by the Wnt receptors Frizzleds, has not been studied. We report here that Frizzled-1 mediates the activation of the canonical Wnt/beta-catenin pathway by Wnt3a in PC12 cells. In addition, the protective effect of Wnt3a against the toxicity of Abeta oligomers was modulated by Frizzled-1 expression levels in both PC12 cells and hippocampal neurons. Over-expression of Frizzled-1 significantly increased cell survival induced by Wnt3a and diminished caspase-3 activation, while knocking-down Frizzled-1 expression by antisense oligonucleotides decreased the Wnt3a protection. Over-expression of wild-type beta-catenin, but not a transcriptionally inactive mutated version, prevented the toxicity of Abeta suggesting that the transcription of Wnt target genes may be involved in these events. This was confirmed by co-transfecting both Frizzled-1 and the inactive form of beta-catenin, which does not elicited protection levels similar to those showed with endogenous beta-catenin. Our results indicate that Wnt3a protects from Abeta-oligomers toxicity by activating the canonical Wnt signaling pathway through the Frizzled-1 receptor, suggesting a therapeutic potential for this signaling pathway in the treatment of Alzheimer's disease.

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