Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight
Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight
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DOI：
10.1016/j.neurobiolaging.2011.07.014
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Beyreuther, Konrad
中科院分区：
文献类型：
--
作者：
Amtul, Zareen;Uhrig, Markus;Beyreuther, Konrad
炎症被认为是阿尔茨海默病（AD）发病机制中不可或缺的一部分。花生四烯酸 (AA) 是最重要的 omega-6 脂肪酸，也是炎症途径的介质。高灵敏酶联免疫吸附试验显示AA及其各种代谢物；前列腺素、血栓素和白三烯 B4 导致 Abeta40 和 42 肽的分泌显着增加。据认为，在 Delta 5 或 7Z、13 或 15E 位（例如 PGE(2)、PGF(2α)、THXB2 和 PGF(2α)EA）或 Delta 6Z、8E、10E、14Z（例如 LB4）位上相同数量的交替顺式和反式双键的组合，被认为是造成这种情况的原因。 因为他们的有害行为。 CP 24,879 和芝麻素（2 种 AA 途径抑制剂）可抑制 β 淀粉样蛋白 (Aβ) 肽的产生。免疫印迹实验和 SP-C99 转染 COS-7 细胞的使用表明，AA 及其代谢物驱动的 Aβ 产生改变是通过淀粉样前体蛋白 (APP) 的 γ 分泌酶裂解介导的。表达人类淀粉样前体蛋白双突变形式的早发 AD 转基因小鼠模型瑞典 (K670N/M671L) 和印第安纳 (V717F) 证实了我们的体外研究结果，当给它们喂食补充有 2% AA 的食物时，它们的大脑中 Abeta 和淀粉样蛋白斑块水平较高，从而证实了我们的体外研究结果。我们的工作不仅支持AA及其代谢物参与Aβ的产生和AD的发病机制，而且有助于阐明结构-活性关系的各个方面，有助于未来的非甾体抗炎药（NSAID）研究。 (C) 2012 Elsevier Inc. 保留所有权利。
Inflammation is believed to be integral to the pathogenesis of Alzheimer's disease (AD). Arachidonic acid (AA) is the most important omega-6 fatty acid and a mediator of inflammatory pathways. High-sensitivity enzyme linked immunosorbent assay shows that AA and its various metabolites; prostaglandins, thromboxanes, and leukotriene B4 resulted in significantly higher secretion of both Abeta40 and 42 peptides. A combination of identical number of alternate cis and trans double bonds either at positions Delta 5 or 7Z, 13 or 15E (such as PGE(2), PGF(2 alpha), THXB2 and PGF(2 alpha)EA) or at positions Delta 6Z, 8E, 10E, 14Z (such as LB4) built in the 3-dimensional structure of 20-carbon fatty acyl chains believed to be responsible for their detrimental action. CP 24,879 and sesamin, 2 inhibitors of the AA pathway suppressed the production of amyloid-beta (A beta) peptides. Immunoblotting experiments and use of SP-C99 transfected COS-7 cells suggested that AA and its metabolites-driven altered production of A beta is mediated through gamma-secretase cleavage of amyloid precursor protein (APP). An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings by showing higher levels of Abeta and amyloid plaques in the brains, when they were fed chow supplemented with 2% AA. Our work not only supports that AA and its metabolites are involved in the production of A beta and in the pathogenesis of AD but also contributes to clarify aspects of structure-activity relationship helpful for future nonsteroidal anti-inflammatory drugs (NSAIDs) research. (C) 2012 Elsevier Inc. All rights reserved.