title: Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta 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 Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-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.
authors.affiliation: Centro de Regulación Celular y Patología, MIFAB, Facultad de Ciencias Biológicas, P Universidad Católica de Chile, Santiago, Chile.
authors.forename: G V
authors.initials: GV
authors.lastname: De Ferrari
authors.forename: M A
authors.initials: MA
authors.lastname: Chacón
authors.forename: M I
authors.initials: MI
authors.lastname: Barría
authors.forename: J L
authors.initials: JL
authors.lastname: Garrido
authors.forename: J A
authors.initials: JA
authors.lastname: Godoy
authors.forename: G
authors.initials: G
authors.lastname: Olivares
authors.forename: A E
authors.initials: AE
authors.lastname: Reyes
authors.forename: A
authors.initials: A
authors.lastname: Alvarez
authors.forename: M
authors.initials: M
authors.lastname: Bronfman
authors.forename: N C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008094:Lithium / Q000494:pharmacology; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin
chemical_list: D016229:Amyloid beta-Peptides; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D011506:Proteins; D015534:Trans-Activators; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D008094:Lithium; D011493:Protein Kinase C