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

G. V. De Ferrari, M. A. Chacón, M. I. Barría, J. L. Garrido, J. A. Godoy, G. Olivares, A. E. Reyes, A. Alvarez, M. Bronfman, N. C. Inestrosa

Resultado de la investigación: Contribución a una revistaArtículo

267 Citas (Scopus)

Resumen

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid β-peptide (Aβ). We report here molecular changes induced by Aβ, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Aβ fibrils, as an in vivo model of the disease. Results indicate that in both systems, Aβ 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-3β promoted the survival of post-mitotic neurons against Aβ neurotoxicity and recovered cytosolic β-catenin to control levels. Moreover, the neurotoxic effect of Aβ 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 Aβ 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 Aβ. Our results are consistent with the idea that Aβ-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.

Idioma originalInglés
Páginas (desde-hasta)195-208
Número de páginas14
PublicaciónMolecular Psychiatry
Volumen8
N.º2
DOI
EstadoPublicada - 24 mar 2003

Áreas temáticas de ASJC Scopus

  • Biología molecular
  • Psiquiatría y salud mental
  • Neurociencia celular y molecular

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    De Ferrari, G. V., Chacón, M. A., Barría, M. I., Garrido, J. L., Godoy, J. A., Olivares, G., Reyes, A. E., Alvarez, A., Bronfman, M., & Inestrosa, N. C. (2003). Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils. Molecular Psychiatry, 8(2), 195-208. https://doi.org/10.1038/sj.mp.4001208