Distribution, levels, and activation of MEK1 in Alzheimer's disease
Distribution, levels, and activation of MEK1 in Alzheimer's disease
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DOI：
10.1046/j.1471-4159.2003.01820.x
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Smith, MA
中科院分区：
文献类型：
--
作者：
Zhu, XW;Sun, Z;Smith, MA
细胞外信号调节激酶（ERK）参与了阿尔茨海默病（AD）的发病机制，但导致ERK激活的上游级联反应尚未阐明。本研究主要研究ERK的生理激活剂之一丝裂原活化蛋白激酶（MAPK）/ERK激酶1（MEK 1）。虽然AD和年龄匹配的对照病例之间总MEK 1的水平和分布没有显著差异，但激活的磷酸化MEK 1水平的增加特异性地定位于严重AD（Braak阶段V-VI）的神经元胞浆内颗粒结构。MEK 1及其下游效应子磷酸化ERK之间的相当大的重叠表明了功能和机制联系。磷酸-MEK 1的核定位在轻度AD病例（Braak阶段III-IV）和具有有限病理学的对照病例（Braak阶段I-II）中均是显著特征。由于MEK 1通常是胞质的，因为它的氨基末端存在核输出信号，从核的主动输出，我们怀疑，在早期阶段的AD患者的磷酸化MEK 1的明显的核积累表明，异常的核运输可能有助于AD的发病机制。通过免疫印迹分析，磷酸-MEK 1在AD中比对照病例显著增加。总之，这些发现进一步证实了ERK通路在AD中失调的观点，并且还表明该通路在疾病发病机制中的积极作用。
Extracellular-signal-regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen-activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age-matched control cases, increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V-VI). The considerable overlap between MEK1 and its downstream effector, phospho-ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho-MEK1 was a prominent feature in both mild AD cases (Braak stage III-IV) and control cases with limited pathology (Braak stage I-II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino-terminus, we suspect that the apparent nuclear accumulation of phospho-MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho-MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.