¹Centro de Regulación Celular y Patología, MIFAB, Facultad de Ciencias Biológicas, P Universidad Católica de Chile, Santiago, Chile

Correspondence: Prof NC Inestrosa, Molecular Neurobiology Unit, P Catholic University of Chile, PO Box 114-D, Santiago, Chile. E-mail: ninestr@genes.bio.puc.cl

Received 26 July 2001; Revised 7 April 2002; Accepted 23 April 2002.

Abstract

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