Increased level of active GSK-3β in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration
Increased level of active GSK-3β in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration
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DOI：
10.1111/j.1365-2990.2006.00795.x
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发表时间：
2007-02-01
影响因子：
5
通讯作者：
Brion, J. -P.
中科院分区：
文献类型：
--
作者：
Leroy, K.;Yilmaz, Z.;Brion, J. -P.
过度磷酸化tau蛋白的体树突积累是阿尔茨海默病（AD）中神经元缠结（NFT）出现之前的早期事件，并且可能是其形成所必需的。糖原合成酶激酶-3 β（GSK-3 β）是tau的生理激酶，其产生在NFT和其他tau阳性内含物中鉴定的许多tau磷酸化位点。我们研究了AD患者、嗜银颗粒病和弥漫性路易体病中GSK-3 β活性形式（GSK-3 pTyr 216）的细胞分布和表达。通过Western blotting分析，在AD患者的额叶皮层中观察到GSK-3（pTyr 216）的水平显著增加。一群神经元显示GSK-3（pTyr 216）的体树突蓄积，但GSK-3 β（GSK-3 pSer 9）的失活形式未蓄积。这些GSK-3（pTyr 216）阳性细胞中的大多数对已知由GSK-3 β产生的六种不同磷酸tau表位呈阳性。通过使用GSK-3（pTyr 216）和磷酸化tau免疫标记结合Gallyas和DAPI染色的四重标记方法，我们检查了神经元含有体树突GSK-3（pTyr 216）免疫反应性在不同阶段的神经变性。大多数神经元在pretangle阶段没有Gallyas阳性夹杂物的GSK-3（pTyr 216）阳性，这种GSK-3（pTyr 216）的免疫反应性仍然在大多数细胞含有Gallyas和磷酸化tau阳性夹杂物，除了在细胞外NFT。GSK-3（pTyr 216）免疫反应性存在于嗜银颗粒，但不是在皮质路易体。这些结果直接表明，GSK-3 β的活性在AD中增加，并且GSK-3 β的体树突积累和激活是NFT和其他tau阳性内含物形成之前和伴随的早期事件。
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-3 beta (GSK-3 beta) 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-3 beta (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-3 beta (GSK-3 pSer9). Most of these GSK-3 (pTyr216)-positive cells were positive for six different phosphotau epitopes known to be generated by GSK-3 beta. 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-3 beta is increased in AD and that somatodendritic accumulation and activation of GSK-3 beta is an early event preceding and accompanying the formation of NFT and of other tau-positive inclusions.