Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: A redox proteomics analysis
Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: A redox proteomics analysis
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DOI：
10.1016/j.neurobiolaging.2005.05.005
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发表时间：
2006-07-01
影响因子：
4.2
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Sultana, Rukhsana;Boyd-Kimball, Debra;Butterfield, D. Allan
阿尔茨海默病（AD）在神经病理学上的特征是细胞内神经原纤维缠结（NFT）和细胞外老年斑（SP），老年斑的核心是由淀粉样前体蛋白（APP）（一种跨膜蛋白）衍生的β - 淀粉样肽（Aβ）。据报道，AD患者的大脑处于氧化应激状态，这可能在AD的发病机制和进展中起重要作用。目前的蛋白质组学研究重点是鉴定AD海马中与氧化应激在AD中的作用相关的蛋白质氧化的特定靶点。在此，我们报道蛋白质Pin1在AD海马中显著下调且被氧化。Pin1的身份通过免疫化学方法得到确认。对AD大脑中Pin1活性的分析以及对单独氧化的纯Pin1的分析表明，Pin1的氧化导致其活性丧失。Pin1涉及细胞周期调控、tau蛋白去磷酸化的多个方面，也与AD有关。本研究通过蛋白质组学在AD海马中发现的Pin1的体内氧化修饰表明，氧化修饰可能与已知的Pin1异构酶活性丧失有关，这在AD神经原纤维病理中可能至关重要。综上所述，这些结果提供了证据，支持神经元Pin1的氧化损伤与AD病理生物学之间存在直接联系。（c）2005爱思唯尔公司。保留所有权利。
Alzheimer disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFT) and of extracellular senile plaques (SP), the central core of which is amyloid beta-peptide (A beta) derived from amyloid precursor protein (APP), a transmembrane protein. AD brain has been reported to be under oxidative stress that may play an important role in the pathogenesis and progression of AD. The present proteomics study is focused on identification of a specific target of protein oxidation in AD hippocampus that has relevance to the role of oxidative stress in AD. Here, we report that the protein, Pin1, is significantly down-regulated and oxidized in AD hippocampus. The identity of Pin1 was confirmed immunochemically. Analysis of Pin1 activity in AD brain and separately as oxidized pure Pin1 demonstrated that oxidation of Pin1 led to loss of activity. Pin1 has been implicated in multiple aspects of cell cycle regulation and dephosphorylation of tau protein as well as in AD. The in vivo oxidative modification of Pin1 as found by proteomics in AD hippocampus in the present study suggests that oxidative modification may be related to the known loss of Pin1 isomerase activity that could be crucial in AD neurofibrillary pathology. Taken together, these results provide evidence supporting a direct link between oxidative damage to neuronal Pin1 and the pathobiology of AD. (c) 2005 Elsevier Inc. All rights reserved.