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Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration.
Neuropathol Appl Neurobiol. 2007 Feb; 33(1):43-55.NA

Abstract

The somatodendritic accumulation of hyperphosphorylated tau proteins is an early event preceding the appearance of neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and might be necessary for their formation. Glycogen synthase kinase-3beta (GSK-3beta) is a physiological kinase for tau that generates many tau phosphorylation sites identified in NFT and in other tau-positive inclusions. We have studied the cellular distribution and the expression of the active form of GSK-3beta (GSK-3 pTyr216) in AD patients, in argyrophilic grain disease and in diffuse Lewy body disease. By Western blotting analysis, a significant increase in the level of GSK-3 (pTyr216) was observed in the frontal cortex of AD patients. A population of neurones showed a somatodendritic accumulation of GSK-3 (pTyr216) but not of the inactive form of GSK-3beta (GSK-3 pSer9). Most of these GSK-3 (pTyr216)-positive cells were positive for six different phosphotau epitopes known to be generated by GSK-3beta. By using a quadruple labelling method using GSK-3 (pTyr216) and phosphotau immunolabelling combined with Gallyas and DAPI staining, we examined neurones containing a somatodendritic GSK-3 (pTyr216) immunoreactivity at different stages of neurodegeneration. A majority of neurones at the pretangle stage without Gallyas-positive inclusions were GSK-3 (pTyr216) positive and this GSK-3 (pTyr216) immunoreactivity remained in most cells containing Gallyas and phosphotau-positive inclusions excepted in extracellular NFT. A GSK-3 (pTyr216) immunoreactivity was present in argyrophilic grains but not in cortical Lewy bodies. These results directly suggest that the activity of GSK-3beta is increased in AD and that somatodendritic accumulation and activation of GSK-3beta is an early event preceding and accompanying the formation of NFT and of other tau-positive inclusions.

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Authors+Show Affiliations

Leroy K
Laboratory of Histology, Neuroanatomy and Neuropathology, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium.
Yilmaz Z
No affiliation info available
Brion JP
No affiliation info available

MeSH

AgedAged, 80 and overAlzheimer DiseaseCell NucleusDendritesEpitopesFemaleFluorescent DyesGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansImmunoblottingImmunohistochemistryIndolesLewy Body DiseaseMaleMiddle AgedNeurofibrillary TanglesNeuronsPhosphorylationPrefrontal Cortextau Proteins

Pub Type(s)

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

Language

eng

PubMed ID

17239007

Citation

Leroy, K, et al. "Increased Level of Active GSK-3beta in Alzheimer's Disease and Accumulation in Argyrophilic Grains and in Neurones at Different Stages of Neurofibrillary Degeneration." Neuropathology and Applied Neurobiology, vol. 33, no. 1, 2007, pp. 43-55.
Leroy K, Yilmaz Z, Brion JP. Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol. 2007;33(1):43-55.
Leroy, K., Yilmaz, Z., & Brion, J. P. (2007). Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathology and Applied Neurobiology, 33(1), 43-55.
Leroy K, Yilmaz Z, Brion JP. Increased Level of Active GSK-3beta in Alzheimer's Disease and Accumulation in Argyrophilic Grains and in Neurones at Different Stages of Neurofibrillary Degeneration. Neuropathol Appl Neurobiol. 2007;33(1):43-55. PubMed PMID: 17239007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. AU - Leroy,K, AU - Yilmaz,Z, AU - Brion,J-P, PY - 2007/1/24/pubmed PY - 2007/2/27/medline PY - 2007/1/24/entrez SP - 43 EP - 55 JF - Neuropathology and applied neurobiology JO - Neuropathol Appl Neurobiol VL - 33 IS - 1 N2 - The somatodendritic accumulation of hyperphosphorylated tau proteins is an early event preceding the appearance of neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and might be necessary for their formation. Glycogen synthase kinase-3beta (GSK-3beta) is a physiological kinase for tau that generates many tau phosphorylation sites identified in NFT and in other tau-positive inclusions. We have studied the cellular distribution and the expression of the active form of GSK-3beta (GSK-3 pTyr216) in AD patients, in argyrophilic grain disease and in diffuse Lewy body disease. By Western blotting analysis, a significant increase in the level of GSK-3 (pTyr216) was observed in the frontal cortex of AD patients. A population of neurones showed a somatodendritic accumulation of GSK-3 (pTyr216) but not of the inactive form of GSK-3beta (GSK-3 pSer9). Most of these GSK-3 (pTyr216)-positive cells were positive for six different phosphotau epitopes known to be generated by GSK-3beta. By using a quadruple labelling method using GSK-3 (pTyr216) and phosphotau immunolabelling combined with Gallyas and DAPI staining, we examined neurones containing a somatodendritic GSK-3 (pTyr216) immunoreactivity at different stages of neurodegeneration. A majority of neurones at the pretangle stage without Gallyas-positive inclusions were GSK-3 (pTyr216) positive and this GSK-3 (pTyr216) immunoreactivity remained in most cells containing Gallyas and phosphotau-positive inclusions excepted in extracellular NFT. A GSK-3 (pTyr216) immunoreactivity was present in argyrophilic grains but not in cortical Lewy bodies. These results directly suggest that the activity of GSK-3beta is increased in AD and that somatodendritic accumulation and activation of GSK-3beta is an early event preceding and accompanying the formation of NFT and of other tau-positive inclusions. SN - 0305-1846 UR - https://www.unboundmedicine.com/medline/citation/17239007/Increased_level_of_active_GSK_3beta_in_Alzheimer's_disease_and_accumulation_in_argyrophilic_grains_and_in_neurones_at_different_stages_of_neurofibrillary_degeneration_ L2 - https://doi.org/10.1111/j.1365-2990.2006.00795.x DB - PRIME DP - Unbound Medicine ER -