Keap1 Is Localized in Neuronal and Glial Cytoplasmic Inclusions in Various Neurodegenerative Diseases
Keap1 Is Localized in Neuronal and Glial Cytoplasmic Inclusions in Various Neurodegenerative Diseases
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DOI：
10.1097/nen.0b013e31827b5713
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发表时间：
2013-01
影响因子：
3.2
通讯作者：
K. Tanji;Atsushi Maruyama;S. Odagiri;F. Mori;K. Itoh;A. Kakita;H. Takahashi;K. Wakabayashi
中科院分区：
文献类型：
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作者：
K. Tanji;Atsushi Maruyama;S. Odagiri;F. Mori;K. Itoh;A. Kakita;H. Takahashi;K. Wakabayashi
摘要氧化应激被认为是阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）等神经退行性疾病的潜在发病机制。在氧化应激反应中，通过改变Kelch样ECH相关蛋白1（Keap 1）和NF-E2相关因子2（Nrf 2）系统，许多细胞保护产物的水平增加。已知Nrf 2靶点之一p62被掺入神经退行性疾病中的广谱细胞质内含物中，并与Keap 1相互作用。然而，目前尚不清楚Keap 1是否与神经退行性疾病的发病机制有关。在这项研究中，我们调查了AD，PD，路易体痴呆（DLB）和ALS患者脑中p62和Keap 1之间的关系。生化分析表明，p62和Keap 1在AD和DLB脑中相互作用，并被提取到类似的洗涤剂可溶性和不溶性组分中。病理学检查表明，抗Keap 1抗体免疫染色路易体在PD和DLB，神经元缠结在AD，和绞样夹杂物在ALS。进一步的分析表明，与对照组相比，AD患者的共同Nrf 2靶基因水平升高。然而，相对于对照，DLB中Nrf 2靶基因的水平没有统计学显著性。我们的病理和生化结果表明，应激反应的分子基础，参与细胞质包涵体的形成中观察到的几种神经退行性疾病。
Abstract Oxidative stress has been proposed as a potential mechanism for neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). In response to oxidative stress, the levels of numerous cytoprotectiveproducts are increased via alteration of the Kelch-like ECH-associatedprotein 1 (Keap1) and NF-E2–related factor 2 (Nrf2) system. One of the Nrf2 targets, p62, has been known to be incorporated into a wide spectrum of cytoplasmic inclusions in neurodegenerative diseases and interact with Keap1. However, it remains unclear whether Keap1 is associated with the pathogenesis of neurodegenerative diseases. In this study, we investigated the relationship between p62 and Keap1 in the brains of patients with AD, PD, dementia with Lewy bodies (DLB), and ALS. Biochemical analysesshowed that p62 and Keap1 interacted with each other in AD andDLB brains and were extracted into similar detergent-soluble and -insoluble fractions. Pathologic examination demonstrated that anti-Keap1 antibodies immunostained Lewy bodies in PD and DLB, neurofibrillary tangles in AD, and skeinlike inclusions in ALS. Further analysis showed that the levels of common Nrf2 target genes were increased in AD compared with those in controls. However, there were no statistical significances in the levels of Nrf2 target genes in DLB relative to controls. Our pathologic and biochemical results suggest a molecular basis for stress response to be involved in the formation of cytoplasmic inclusions observed in several neurodegenerative diseases.