Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight

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• 作者：Zareen Amtul^a ; ^b ; ^{zamtul@uwo.ca} ; Markus Uhrig^a ; Lin Wang^b ; ^c ; Richard F. Rozmahel^b ; ^c ; Konrad Beyreuther^d
• 关键词：Arachidonic acid ; COS-7 cells ; Structural template ; Transgenic mice ; Alzheimer's disease
• 刊名：Neurobiology of Aging
• 出版年：2012
• 出版时间：April 2012
• 年：2012
• 卷：33
• 期：4
• 页码：831.e21-831.e31
• 全文大小：2566 K

文摘

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 ¦¤5 or 7Z,13 or 15E (such as PGE₂, PGF_2¦Á, THXB2 and PGF_2¦ÁEA) or at positions ¦¤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¦Â) peptides. Immunoblotting experiments and use of SP-C99 transfected COS-7 cells suggested that AA and its metabolites-driven altered production of A¦Â 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¦Â 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.