The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer's disease
The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer's disease
复制标题
DOI：
10.1007/s004010100435
复制
发表时间：
2002-02
影响因子：
12.7
通讯作者：
K. Leroy;A. Boutajangout;M. Authelet;J. Woodgett;B. Anderton;J. Brion
中科院分区：
文献类型：
--
作者：
K. Leroy;A. Boutajangout;M. Authelet;J. Woodgett;B. Anderton;J. Brion
糖原合成酶激酶-3 β（Glycogen synthase kinase-3β，GSK-3β）是一种tau蛋白的生理性激酶，是参与阿尔茨海默病（Alzheimer's disease，AD）中神经元缠结（neurological tangles，NFT）的成对螺旋丝（pairing helical filament，PHF）-tau蛋白过度磷酸化的候选蛋白激酶。GSK-3β也是几个信号级联（包括细胞死亡级联）的关键元件。我们研究了GSK-3在AD中的免疫细胞化学定位。神经元表现出强烈的GSK-3免疫反应颗粒观察到AD，与对照组相比，具有更高的频率。发现这种免疫反应性与颗粒空泡变性（GVD）共定位，并与颗粒空泡体的颗粒相关。GVD颗粒显示出强烈的GSK-3α和GSK-3β免疫反应性，这种免疫反应性可被重组GSK-3预吸收所消除。此外，用抗GSK-3的酪氨酸磷酸化和活性形式的抗体观察到GVD免疫反应性。颗粒空泡变性的一些颗粒也被含有插入片段1（外显子2）的tau亚型特异性抗体以及对Ser 262上磷酸化的tau和Thr 212/Ser 214上磷酸化的tau（GSK-3α和β在体外产生的两个磷酸化位点）特异性抗体强烈标记。GSK-3β在含有NFT的神经元中表达，但仅观察到小部分细胞内NFT呈GSK-3β免疫反应性。对富含PHF-tau的组分进行免疫印迹分析并未发现这些组分中存在任何GSK-3β免疫反应性，表明GSK-3β仅与NFT松散相关。这些结果表明，神经元发展GVD隔离的活性，潜在的有害，GSK-3的形式在这个区室和增加GSK-3免疫反应性的神经元的子集定量区分正常老化从AD。
Glycogen synthase kinase-3β (GSK-3β) 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-3β 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-3α and GSK-3β 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-3α and β. GSK-3β was expressed in neurons containing NFT but only a small proportion of intracellular NFT were observed to be GSK-3β immunoreactive. Immunoblotting analysis of fractions enriched in PHF-tau did not reveal any GSK-3β immunoreactivity in these fractions, indicating that GSK-3β 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.