The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease

Acta Neuropathol. 2002 Feb;103(2):91-9. doi: 10.1007/s004010100435. Epub 2001 Nov 29.

Abstract

Glycogen synthase kinase-3beta (GSK-3beta) is a physiological kinase for tau and is a candidate protein kinase involved in the hyperphosphorylation of tau present in paired helical filament (PHF)-tau of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). GSK-3beta is also a key element of several signaling cascades (including cell death cascades). We have investigated the immunocytochemical localization of GSK-3 immunoreactivity in AD. Neurons exhibiting strongly GSK-3-immunoreactive granules were observed in AD, with a much higher frequency than in control subjects. This immunoreactivity was found to co-localize with the granulovacuolar degeneration (GVD) and to be associated with the granules of the granulovacuolar bodies. The GVD granules showed a strong GSK-3alpha and GSK-3beta immunoreactivity, and this immunoreactivity was abolished by preabsorption with recombinant GSK-3. In addition, the GVD immunoreactivity was observed with an antibody against the tyrosine-phosphorylated and active form of GSK-3. Some granules of the granulovacuolar degeneration were also intensely labeled with an antibody specific for tau isoforms containing insert 1 (exon 2) and with antibodies specific for tau phosphorylated on Ser262 and for tau phosphorylated on Thr212/Ser214, two phosphorylation sites generated in vitro by GSK-3alpha and beta. GSK-3beta was expressed in neurons containing NFT but only a small proportion of intracellular NFT were observed to be GSK-3beta immunoreactive. Immunoblotting analysis of fractions enriched in PHF-tau did not reveal any GSK-3beta immunoreactivity in these fractions, indicating that GSK-3beta was only loosely associated to NFT. These results suggest that neurons developing GVD sequester an active, potentially deleterious, form of GSK-3 in this compartment and that increased GSK-3 immunoreactivity in a subset of neurons quantitatively differentiates normal aging from AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / immunology*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Calcium-Calmodulin-Dependent Protein Kinases / immunology*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Granulocytes / immunology*
  • Granulocytes / metabolism*
  • Granulocytes / pathology
  • Hippocampus / immunology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • In Vitro Techniques
  • Nerve Degeneration / immunology*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Parahippocampal Gyrus / immunology
  • Parahippocampal Gyrus / metabolism
  • Parahippocampal Gyrus / pathology
  • Vacuoles / immunology*
  • Vacuoles / metabolism*
  • Vacuoles / pathology
  • tau Proteins / immunology
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3