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

De Ferrari, GV; Chacón MA; Barría MI; garrido, JL; Godoy JA; Olivares, G; Reyes, AE; Alvarez A.; Bronfman, M; Inestrosa, NC

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.

Más información

Título según WOS: Activation of Wnt signaling and behavioral impairments rescues neurodegeneration induced by beta-amyloid fibrils
Título según SCOPUS: Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by ?-amyloid fibrils
Título de la Revista: MOLECULAR PSYCHIATRY
Volumen: 8
Número: 2
Editorial: SPRINGERNATURE
Fecha de publicación: 2003
Página de inicio: 195
Página final: 208
Idioma: English
URL: http://www.nature.com/doifinder/10.1038/sj.mp.4001208
DOI:

10.1038/sj.mp.4001208

Notas: ISI, SCOPUS