Role of GSK-3beta activation and alpha7 nAChRs in Abeta(1-42)-induced tau phosphorylation in PC12 cells

J Neurochem. 2008 Aug;106(3):1371-7. doi: 10.1111/j.1471-4159.2008.05483.x. Epub 2008 May 15.


Beta-amyloid peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Abeta(1-42) can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Abeta(1-42)-induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Abeta(1-42) increased phosphorylation of tau at serine-202 as detected by AT8 antibody. This Abeta(1-42)-induced tau phosphorylation paralleled phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at tyrosine-216 (GSK-3beta-pY216), which was partially inhibited by the GSK-3beta inhibitor, CHIR98023. Abeta(1-42)-induced tau phosphorylation and increase in GSK-3beta-pY216 phosphorylation were also partially attenuated by alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) selective ligands including agonist A-582941 and antagonists methyllycaconitine and alpha-bungarotoxin. The alpha7 nAChR agonist and the GSK-3beta inhibitor had no additive effect. These observations suggest that alpha7 nAChR modulation can influence Abeta(1-42)-induced tau phosphorylation, possibly involving GSK-3beta. This study provides evidence of nAChR mechanisms underlying Abeta(1-42) toxicity and tau phosphorylation, which, if translated in vivo, could provide additional basis for the utility of alpha7 nAChR ligands in the treatment of Alzheimer's disease.

Publication types

  • Comparative Study

MeSH terms

  • Amyloid beta-Peptides / physiology*
  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 / physiology
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Imidazoles / pharmacology
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology
  • PC12 Cells
  • Peptide Fragments / physiology*
  • Phosphorylation
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Receptors, Nicotinic / metabolism
  • Receptors, Nicotinic / physiology*
  • alpha7 Nicotinic Acetylcholine Receptor
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • CHIR98023
  • Chrna7 protein, human
  • Chrna7 protein, mouse
  • Chrna7 protein, rat
  • Enzyme Inhibitors
  • Imidazoles
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Peptide Fragments
  • Pyridines
  • Pyrimidines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-protein (1-42)
  • tau Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3