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

Authors: De Ferrari, GV  Chacon, MA  Barria, MI  Garrido, JL  Godoy, JA  Olivares, G  Reyes, AE  Alvarez, A  Bronfman, M  Inestrosa, NC 
Citation: De Ferrari GV, etal., Mol Psychiatry. 2003 Feb;8(2):195-208.
Pubmed: (View Article at PubMed) PMID:12610652
DOI: Full-text: DOI:10.1038/sj.mp.4001208

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.

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CRRD Object Information
CRRD ID: 10395276
Created: 2015-08-27
Species: All species
Last Modified: 2015-08-27
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.