The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease.
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.
Leroy
Karelle
K
Laboratory of Histology, Neuroanatomy and Neuropathology, Université Libre de Bruxelles, School of Medicine, 808 route de Lennik, Bldg C-10, 1070 Brussels, Belgium.
Boutajangout
Allal
A
Authelet
M
M
Woodgett
James R
JR
Anderton
Brian H
BH
Brion
Jean-Pierre
JP
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000276:immunology* / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006098:Granulocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D009410:Nerve Degeneration / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020534:Parahippocampal Gyrus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014617:Vacuoles / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism
D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3