Role of GSK‐3β activation and α7 nAChRs in Aβ1–42‐induced tau phosphorylation in PC12 cells

Abstract β‐amyloid peptide 1–42 (Aβ 1–42 ) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer’s disease. Emerging evidence indicates that Aβ 1–42 can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Aβ 1–42 ‐induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Aβ 1–42 increased phosphorylation of tau at serine‐202 as detected by AT8 antibody. This Aβ 1–42 ‐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. Aβ 1–42 ‐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 Aβ 1–42 ‐induced tau phosphorylation, possibly involving GSK‐3β. This study provides evidence of nAChR mechanisms underlying Aβ 1–42 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.