Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease
Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease
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DOI：
10.1016/s0169-328x(02)00488-6
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发表时间：
2002-12-30
期刊：
影响因子：
--
通讯作者：
Grundke-Iqbal, I
中科院分区：
文献类型：
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作者：
Pei, JJ;Braak, H;Grundke-Iqbal, I
阿尔茨海默病(AD)中tau蛋白的异常过度磷酸化被认为与丝裂原活化蛋白(MAP)激酶家族的细胞外信号调节蛋白激酶(ERK)有关。ERK被磷酸化，从而被MAP激酶(MEK)激活。在本研究中，我们确定了MEK1/2和ERK1/2的活性形式，即p-MEK1/2和p-ERK1/2在49个根据Braak和Braak的方案分期为神经纤维变化的大脑中的细胞内和区域分布。我们发现p-MEK1/2和p-ERK1/2存在于经鼻内侧投射神经元的神经库变性的初始阶段，并延伸到其他脑区，伴随着神经原纤维的进行性变化，直到Braak期VI。p-MEK1/2和p-ERK1/2的积聚似乎是在角神经元的细胞质中以不同大小的颗粒开始积累，并随着神经库缠结的进行性发展而生长成大的聚集体。I-III期神经原纤维变性无淀粉样蛋白沉积，可见p-MEK1/2和p-ERK1/2积聚。这些数据提供了直接的原位证据，证实了MAPK通路可能参与了tau的过度磷酸化，并且在AD的β-淀粉样蛋白沉积之前存在这种损伤。(C)2002 Elsevier Science B.V.保留所有权利。
The abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) has been proposed to involve the extracellular-signal-regulated protein kinase (ERK) of the mitogen-activated protein (MAP) kinase family. ERK is phosphorylated and thereby activated by MAP kinase kinase (MEK). In the present study, we determined the intracellular and regional distribution of the active forms of both MEK1/2 and ERK1/2, i.e. p-MEK1/2 and p-ERK1/2 in the entorhinal, hippocampal, and temporal cortices of 49 brains staged for neurofibrillary changes according to Braak and Braak's protocol. We found that p-MEK1/2 and p-ERK1/2 were present in the initial stages of neurolibrillary degeneration in the projecting neurons in the transentorhinal region, and extended into other brain regions co-incident with the progressive sequence of neurofibrillary changes up to and including Braak stage VI. It appeared that the accumulation of p-MEK1/2 and p-ERK1/2 was initiated in the cytoplasm of pretangle neurons in varying size granules, which grew into large aggregates co-existing with the progressive development of neurolibrillary tangles. Accumulation of p-MEK1/2 and p-ERK1/2 was found in cases with stages I-III neurofibrillary degeneration, which were devoid of amyloid deposition. These data provide direct in situ evidence consistent with the possible involvement of MAP kinase pathway in the hyperphosphorylation of tau and the presence of this lesion before deposition of beta-amyloid in AD. (C) 2002 Elsevier Science B.V. All rights reserved.