The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and has generated recent interest as a potential drug target for treating neurodegenerative disorders such as Alzheimer's disease (AD). The property of Ca(2+) permeation associated with alpha7 nAChR agonism may lead to Ca(2+)-dependent intracellular signaling that contribute to the procognitive and neuroprotective effects that have been described with this pharmacology. In this study, we investigated whether alpha7 nAChR agonism leads to increased phosphorylation of the inhibitory regulating amino acid residue Ser-9 on GSK3beta, a major kinase responsible for tau hyperphosphorylation in AD neuropathology. Immunohistochemical analysis revealed that the selective alpha7 agonist A-582941 increased S(9)-GSK3beta phosphorylation in mouse cingulate cortex and hippocampus that was not observed in alpha7 nAChR knock-out mice. A-582941 steady state exposure through continuous (2 wk) infusion also increased S(9)-GSK3beta phosphorylation in the hippocampus of Tg2576 (APP), as well as wild-type mice. Moreover, A-582941 continuous infusion decreased phosphorylation of tau in hippocampal CA3 Mossy fibers and spinal motoneurons in a hypothermia-induced tau hyperphosphorylation mouse model and AD double transgenic APP/tau mouse line, respectively. These studies demonstrate that inactivation of GSK3beta may be associated with alpha7 nAChR-induced signaling leading to attenuated tau hyperphosphorylation, raising the intriguing possibility that alpha7 nAChR agonism may have disease modifying benefit in the treatment of tauopathies, in particular AD.