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.2011.12.038
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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）发病机制的组成部分。花生四烯酸（AA）是最重要的ω-6脂肪酸，也是炎症途径的介质。高灵敏度的酶联免疫吸附试验表明，AA及其各种代谢产物，前列腺素，血栓烷，和白三烯B4导致显着更高的分泌两个A β 40和42肽。在20-碳脂肪酰基链的三维结构中，在位置Δ 5或7Z、13或15 E（如PGE（2）、PGF（2 α）、THXB 2和PGF（2 α）EA）或在位置Δ 6 Z、8 E、10 E、14 Z（如LB 4）处的相同数目的交替顺式和反式双键的组合被认为是造成其有害作用的原因。CP 24，879和芝麻素，2种AA途径的抑制剂，抑制淀粉样蛋白-β（A β）肽的产生。免疫印迹实验和使用SP-C99转染的COS-7细胞表明，AA及其代谢物驱动的A β产生的改变是通过γ-分泌酶切割淀粉样前体蛋白（APP）介导的。一种表达人淀粉样前体蛋白双突变形式的早发性AD转基因小鼠模型，瑞典（K670 N/M671 L）和印第安纳州（V717 F），证实了我们的体外研究结果，当它们被喂食补充有2% AA的食物时，大脑中的Abeta和淀粉样斑块水平较高。我们的工作不仅支持AA及其代谢产物参与A β的产生和AD的发病机制，而且有助于澄清有助于未来非甾体抗炎药（NSAID）研究的构效关系。(C)2012 Elsevier Inc. All rights reserved.
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.