Glycogen synthase kinase-3beta is complexed with tau protein in brain microtubules.

  • Sun W
  • Qureshi H
  • Cafferty P
 et al. 
  • 21

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Abstract

In Alzheimer's disease, microtubule-associated protein tau is hyperphosphorylated by an unknown mechanism and is aggregated into paired helical filaments. Hyperphosphorylation causes loss of tau function, microtubule instability, and neurodegeneration. Glycogen synthase kinase-3beta (GSK3beta) has been implicated in the phosphorylation of tau in normal and Alzheimer's disease brain. The molecular mechanism of GSK3beta-tau interaction has not been clarified. In this study, we find that when microtubules are disassembled, microtubule-associated GSK3beta dissociates from microtubules. From a gel filtration column, the dissociated GSK3beta elutes as an approximately 400-kDa complex. When fractions containing the approximately 400-kDa complex are chromatographed through an anti-GSK3beta immunoaffinity column, tau co-elutes with GSK3beta. From fractions containing the approximately 400-kDa complex, both tau and GSK3beta co-immunoprecipitate with each other. GSK3beta binds to nonphosphorylated tau, and the GSK3beta-binding region is located within the N-terminal projection domain of tau. In vitro, GSK3beta associates with microtubules only in the presence of tau. From brain extract, approximately 6-fold more GSK3beta co-immunoprecipitates with tau than GSK3alpha. These data indicate that, in brain, GSK3beta is bound to tau within a approximately 400-kDa microtubule-associated complex, and GSK3beta associates with microtubules via tau.

Author-supplied keywords

  • Alzheimer Disease
  • Alzheimer Disease: metabolism
  • Animals
  • Binding Sites
  • Brain
  • Brain: metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases: meta
  • Cattle
  • Chromatography, Gel
  • Cloning, Molecular
  • DNA, Complementary
  • DNA, Complementary: metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Glutathione Transferase
  • Glutathione Transferase: metabolism
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Immunoblotting
  • Microtubules
  • Microtubules: metabolism
  • Peptides
  • Peptides: chemistry
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • tau Proteins
  • tau Proteins: metabolism

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Authors

  • Wei Sun

  • Hamid Y Qureshi

  • Patrick W Cafferty

  • Kazuya Sobue

  • Alka Agarwal-Mawal

  • Katherine D Neufield

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