Role of GSK-3β activation and α7 nAChRs in Aβ 1-42-induced tau phosphorylation in PC12 cells

Abstract

β-amyloid peptide 1-42 (Aβ1-42) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ1-42 can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Aβ1-42- induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Aβ1-42 increased phosphorylation of tau at serine-202 as detected by AT8 antibody. This Aβ1-42-induced tau phosphorylation paralleled phosphorylation of glycogen synthase kinase-3β (GSK-3β) at tyrosine-216 (GSK-3β-pY216), which was partially inhibited by the GSK-3β inhibitor, CHIR98023. Aβ1-42-induced tau phosphorylation and increase in GSK-3β-pY216 phosphorylation were also partially attenuated by α7 nicotinic acetylcholine receptor (α7 nAChR) selective ligands including agonist A-582941 and antagonists methyllycaconitine and α-bungarotoxin. The α7 nAChR agonist and the GSK-3β inhibitor had no additive effect. These observations suggest that α7 nAChR modulation can influence Aβ1-42-induced tau phosphorylation, possibly involving GSK-3β. This study provides evidence of nAChR mechanisms underlying Aβ1-42 toxicity and tau phosphorylation, which, if translated in vivo, could provide additional basis for the utility of α7 nAChR ligands in the treatment of Alzheimer's disease. © 2008 Abbott Laboratories.