Current advances on different kinases involved in Tau phosphorylation, and implications in Alzheimer's disease and tauopathies
Current advances on different kinases involved in Tau phosphorylation, and implications in Alzheimer's disease and tauopathies
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DOI：
10.2174/1567205052772713
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发表时间：
2005-01-05
影响因子：
2.1
通讯作者：
Avila, J.
中科院分区：
文献类型：
--
作者：
Ferrer, I.;Gomez-Isla, T.;Avila, J.
神经元（和神经胶质细胞）中tau蛋白的过度磷酸化和积累是阿尔茨海默病的主要病理标志之一。s病（AD）和其他tau病，包括匹克病（PiD）、进行性核上性麻痹、皮质基底变性、嗜阿糖颗粒病、家族性额颞叶痴呆和帕金森病，这些疾病与17号染色体由于tau基因（FTDP-17-tau）突变有关。tau的过度磷酸化是由几种激酶调控的，这些激酶在体外磷酸化tau的特定位点。gsk -3免疫沉淀的AD中肌基不溶性组分具有磷酸化重组tau蛋白的能力。此外，GSK-3在Ser9位点磷酸化，使GSK-3失活，在阿尔茨海默病的大多数具有神经原纤维缠结和老年斑营养不良的神经突的神经元中发现，在其他tau病的Pick小体和其他含有磷酸化tau的神经元和胶质细胞中发现。活性激酶的表达增加，包括应激激活激酶，c-Jun n -末端激酶（SAPK/JNK）和激酶p38在所有牛头病的脑匀浆中都被发现。强烈的活性SAPK/JNK和p38免疫反应性已被观察到仅限于含有过度磷酸化tau的神经元和胶质细胞，以及阿尔茨海默病老年斑的营养不良神经突。此外，SAPK/JNK-和p38免疫沉淀亚细胞组分富集异常过度磷酸化的tau，具有磷酸化重组tau和c-Jun和ATF-2的能力，而c-Jun和ATF-2是SAPK/JNK和p38在AD和PiD中的特异性底物。有趣的是，在携带双APP瑞典突变的转基因小鼠（Tg 2576）的大脑中，在β A4淀粉样蛋白沉积物周围，观察到磷酸化（活性）SAPK/JNK和p38以及含有过度磷酸化tau的神经突的表达增加。这些发现表明，β A4淀粉样蛋白具有触发应激激酶激活的能力，应激激酶反过来使淀粉样蛋白沉积物周围神经突中的tau磷酸化。对两名参与β淀粉样蛋白免疫试验并在免疫诱发脑炎过程中死亡的AD患者的尸检报告也有补充发现。脑部神经病理学检查显示大量局灶性淀粉样斑块减少，但未见神经原纤维变性。在Tg2576小鼠和人脑中，SAPK/JNK和p38的激活降低，与淀粉样斑块减少相关的异常神经突的tau过度磷酸化降低。这些发现支持淀粉样蛋白级联假说，即在老年斑营养不良的神经突中应激激酶介导tau磷酸化，但不支持阿尔茨海默病的神经原纤维缠结和神经纤维线。
Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around beta A4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that beta A4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.