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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.AN

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.

Authors+Show Affiliations

Leroy 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 A
No affiliation info available
Authelet M
No affiliation info available
Woodgett JR
No affiliation info available
Anderton BH
No affiliation info available
Brion JP
No affiliation info available

MeSH

AgedAged, 80 and overAlzheimer DiseaseCalcium-Calmodulin-Dependent Protein KinasesGlycogen Synthase Kinase 3Glycogen Synthase KinasesGranulocytesHippocampusHumansIn Vitro TechniquesNerve DegenerationParahippocampal GyrusVacuolestau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11810173

Citation

Leroy, Karelle, et al. "The Active Form of Glycogen Synthase Kinase-3beta Is Associated With Granulovacuolar Degeneration in Neurons in Alzheimer's Disease." Acta Neuropathologica, vol. 103, no. 2, 2002, pp. 91-9.
Leroy K, Boutajangout A, Authelet M, et al. The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. Acta Neuropathol. 2002;103(2):91-9.
Leroy, K., Boutajangout, A., Authelet, M., Woodgett, J. R., Anderton, B. H., & Brion, J. P. (2002). The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. Acta Neuropathologica, 103(2), 91-9.
Leroy K, et al. The Active Form of Glycogen Synthase Kinase-3beta Is Associated With Granulovacuolar Degeneration in Neurons in Alzheimer's Disease. Acta Neuropathol. 2002;103(2):91-9. PubMed PMID: 11810173.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. AU - Leroy,Karelle, AU - Boutajangout,Allal, AU - Authelet,M, AU - Woodgett,James R, AU - Anderton,Brian H, AU - Brion,Jean-Pierre, Y1 - 2001/11/29/ PY - 2001/03/16/received PY - 2002/1/26/pubmed PY - 2002/5/25/medline PY - 2002/1/26/entrez SP - 91 EP - 9 JF - Acta neuropathologica JO - Acta Neuropathol VL - 103 IS - 2 N2 - 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. SN - 0001-6322 UR - https://www.unboundmedicine.com/medline/citation/11810173/The_active_form_of_glycogen_synthase_kinase_3beta_is_associated_with_granulovacuolar_degeneration_in_neurons_in_Alzheimer's_disease_ L2 - https://dx.doi.org/10.1007/s004010100435 DB - PRIME DP - Unbound Medicine ER -