Journal Article

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

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

2003

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Alzheimer Disease - drug therapy / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Animals / Behavior, Animal - drug effects / Behavioral Sciences / beta Catenin / Biological and medical sciences / Biological Psychology / Cell culture / Cell Death - drug effects / Cell Death - physiology / Cells, Cultured / Culture Media, Conditioned - pharmacology / Cytoskeletal Proteins - metabolism / Cytotoxicity / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Fibrils / Glycogen / Glycogen synthase kinase 3 / Humans / immediate-communication / Isoenzymes - metabolism / Kidney - cytology / Kinases / Lithium / Lithium - pharmacology / Lithium chloride / Medical sciences / Medicine / Medicine & Public Health / Memory Disorders - metabolism / Memory Disorders - pathology / Mice / Nerve Degeneration - drug therapy / Nerve Degeneration - metabolism / Nerve Degeneration - pathology / Neurodegeneration / Neurodegenerative diseases / Neurology / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neurosciences / Neurotoxicity / Pharmacotherapy / Protein kinase C / Protein Kinase C - metabolism / Proteins - genetics / Proteins - metabolism / Psychiatry / Rats / Rats, Sprague-Dawley / Signal transduction / Signal Transduction - physiology / Spatial discrimination learning / Spatial memory / Trans-Activators - metabolism / Transfection / Tropical medicine / Wnt protein / Wnt Proteins / Wnt3 Protein / Wnt3A Protein / β-Amyloid / β-Catenin