Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid β -peptide (A β ). We report here molecular changes induced by A β , both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed A β fibrils, as an in vivo model of the disease. Results indicate that in both systems, A β neurotoxicity resulted in the destabilization of endogenous levels of β -catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3 β promoted the survival of post-mitotic neurons against A β neurotoxicity and recovered cytosolic β -catenin to control levels. Moreover, the neurotoxic effect of A β 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 A β fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing β -catenin levels and improved the deficit in spatial learning induced by A β . Our results are consistent with the idea that A β -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.