Phosphorylation of tau and α-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer's disease, and in Parkinson's disease and related α-synucleinopathies
Phosphorylation of tau and α-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer's disease, and in Parkinson's disease and related α-synucleinopathies
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DOI：
10.1016/j.neuroscience.2008.01.030
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发表时间：
2008-04-09
期刊：
影响因子：
3.3
通讯作者：
Ferrer, I.
中科院分区：
文献类型：
--
作者：
Muntane, G.;Dalfo, E.;Ferrer, I.
tau磷酸化和a-突触核蛋白磷酸化分别是阿尔茨海默病（AD）和α -突触核蛋白病（帕金森病：PD和路易体痴呆：DLB）的关键异常。采用亚分离、凝胶电泳和Western blotting检测不同进展阶段AD患者、PD、DLB纯型和普通型以及年龄匹配对照组额叶皮层中磷酸tau蛋白的存在和分布。Phospho-tauSer396在阿尔茨海默病额叶皮层的内嗅/经内嗅、边缘和新皮层阶段的突触富集部分中被发现，这表明在阿尔茨海默病额叶皮层发生神经原纤维缠结之前，突触就发生了早期的tau磷酸化。Phospho-tauSer396也存在于PD和DLB纯形式和普通形式的额叶皮层突触富集部分，从而表明在这些α -突触核蛋白病的突触中tau磷酸化增加。密度测定研究显示，在阿尔茨海默病I - III期、PD和DLB的额叶皮层突触富集部分中，与tau-13相关的磷酸化- tauser396在20%至40%之间。在AD V期和DLB普通形态中，这一比例约为95%。然而，正如AT8抗体所揭示的那样，神经原纤维缠结的tau磷酸化特征仅在阿尔茨海默病晚期在额叶皮层的突触部分发现。在PD和DLB的纯和普通形式以及AD的晚期，在额叶皮层的突触富集部分中观察到磷酸化的α - synucleinser129水平升高。由于tau过度磷酸化与微管组装有关，而a-synuclein Ser129位点的磷酸化有利于α -synuclein聚集，因此可以认为突触是两组疾病中tau和a-synuclein异常磷酸化的靶点。在携带A53T α -突触核蛋白突变的12月龄转基因小鼠的突触富集部分中也发现了Tau蛋白Ser396位点的磷酸化。(c) 2008 IBRO。Elsevier Ltd.出版。版权所有。
Phosphorylation of tau and phosphorylation of a-synuclein are crucial abnormalities in Alzheimer's disease (AD) and alpha-synucleinopathies (Parkinson's disease: PD, and dementia with Lewy bodies: DLB), respectively. The presence and distribution of phospho-tau were examined by sub-fractionation, gel electrophoresis and Western blotting in the frontal cortex of cases with AD at different stages of disease progression, PD, DLB pure form and common form, and in age-matched controls. Phospho-tauSer396 has been found in synaptic-enriched fractions in AD frontal cortex at entorhinal/transentorhinal, limbic and neocortical stages, thus indicating early tau phosphorylation at the synapses in AD before the occurrence of neurofibrillary tangles in the frontal cortex. Phospho-tauSer396 is also found in synaptic-enriched fractions in the frontal cortex in PD and DLB pure and common forms, thus indicating increased tau phosphorylation at the synapses in these alpha-synucleinopathies. Densitometric studies show between 20% and 40% phospho-tauSer396, in relation with tau-13, in synaptic-enriched fractions of the frontal cortex in AD stages I - III, and in PD and DLB. The percentage reaches about 95% in AD stage V and DLB common form. Yet tau phosphorylation characteristic of neurofibrillary tangles, as revealed with the AT8 antibody, is found in the synaptic fractions of the frontal cortex only at advanced stages of AD. Increased phosphorylated alpha-synucleinSer129 levels are observed in the synaptic-enriched fractions of the frontal cortex in PD and DLB pure and common forms, and in advanced stages of AD. Since tau-hyperphosphorylation has implications in microtubule assembly, and phosphorylation of a-synuclein at Ser129 favors alpha-synuclein aggregation, it can be suggested that synapses are targets of abnormal tau and a-synuclein phosphorylation in both groups of diseases. Tau phosphorylation at Ser396 has also been found in synapticenriched fractions in 12-month-old transgenic mice bearing the A53T alpha-synuclein mutation. (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.