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

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.