title: Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons.
abstract: Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary lesions associated with Alzheimer's disease. Hyperphosphorylation reduces the affinity of tau for microtubules and is thought to be a critical event in the pathogenesis of this disease. Recently, glycogen-synthase kinase-3 has been shown to phosphorylate tau in vitro and in non-neuronal cells transfected with tau. The activity of glycogen-synthase kinase-3 can be down-regulated in response to insulin or insulin-like growth factor-1 through the activation of the phosphatidylinositol 3-kinase pathway. We therefore hypothesize that insulin or insulin-like growth factor-1 may affect tau phosphorylation through the inhibition of glycogen-synthase kinase-3 in neurons. Using cultured human neuronal NT2N cells, we demonstrate that glycogen-synthase kinase-3 phosphorylates tau and reduces its affinity for microtubules and that insulin and insulin-like growth factor-1 stimulation reduces tau phosphorylation and promotes tau binding to microtubules. We further demonstrate that these effects of insulin and insulin-like growth factor-1 are mediated through the inhibition of glycogen-synthase kinase-3 via the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hong
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002478:Cells, Cultured; D004258:DNA Polymerase III; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004258:DNA Polymerase III; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C041273:transcription factor tau