Role of GSK-3beta activation and alpha7 nAChRs in Abeta(1-42)-induced tau phosphorylation in PC12 cells.
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.
Hu
Min
M
Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064-6125, USA.
Waring
Jeffrey F
JF
Gopalakrishnan
Murali
M
Li
Jinhe
J
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000502:physiology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C467064:CHIR98023; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011725:Pyridines; D011743:Pyrimidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3