Abstract

An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-beta (A beta) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the alpha 7-nicotinic acetylcholine receptor (alpha 7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective alpha 7-nAChR agonist, protects from morphological and synaptic impairments induced by A beta oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by A beta oligomers through the alpha 7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between alpha 7-nAChR and the Wnt/beta-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes beta-catenin, in a concentration-dependent manner; (2) nicotine prevents A beta-induced loss of beta-catenin through the alpha 7-nAChR; and (3) activation of canonical Wnt/beta-catenin signaling induces alpha 7-nAChR expression. Analysis of the alpha 7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by A beta oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the alpha 7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.