M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity. A role for Wnt signaling pathway.

Abstract	Amyloid-beta-peptide (Abeta) deposits are one of the hallmark features of Alzheimer's disease. Signal transduction alterations are implicate in the neuronal responses to Abeta, which include neurotransmitter systems and pathways involved in the maintenance of the nervous system. In this context, we have recently found that Abeta-neurotoxicity triggers a loss of Wnt signaling. We report here that M1-acetylcholine-muscarinic-receptor (mAChR) activation protects neurons from Abeta-toxicity. Concomitant with this effect, a modulation of the Wnt signaling was observed. M1 mAChR activation inhibits glycogen-synthase-kinase-3beta (GSK-3beta) activity, stabilizes cytoplasmic and nuclear beta-catenin, and induces the expression of the Wnt target genes engrailed and cyclin-D1, reverting the switch off of the Wnt pathway caused by Abeta-toxicity. Neurons from mice that overexpress GSK-3beta allow us to establish that M1 mAChR stimulation leads to GSK-3beta inactivation. We conclude that the cross-talk between the muscarinic signaling and Wnt components underlie the neuroprotective effect of the M1 mAChR activation.
Authors	Ginny G Farías, Juan A Godoy, Félix Hernández, Jesús Avila, Abraham Fisher, Nibaldo C Inestrosa
Journal	Neurobiology of disease (Neurobiol Dis) Vol. 17 Issue 2 Pg. 337-48 (Nov 2004) ISSN: 0969-9961 [Print] United States
PMID	15474371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amyloid beta-Peptides CTNNB1 protein, mouse Ctnnb1 protein, rat Cytoskeletal Proteins Peptide Fragments Proto-Oncogene Proteins Receptor, Muscarinic M1 Trans-Activators Wnt Proteins amyloid beta-protein (1-40) beta Catenin Glycogen Synthase Kinase 3 beta Gsk3b protein, mouse Gsk3b protein, rat Glycogen Synthase Kinase 3
Topics	Amyloid beta-Peptides (poisoning) Animals Cells, Cultured Cytoprotection Cytoskeletal Proteins (antagonists & inhibitors, metabolism) Embryo, Mammalian Glycogen Synthase Kinase 3 (antagonists & inhibitors) Glycogen Synthase Kinase 3 beta Hippocampus (cytology, drug effects) Mice Mice, Transgenic Neurons (drug effects) Peptide Fragments (poisoning) Proto-Oncogene Proteins (physiology) Rats Rats, Sprague-Dawley Receptor, Muscarinic M1 (physiology) Signal Transduction (physiology) Trans-Activators (antagonists & inhibitors, metabolism) Wnt Proteins beta Catenin

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