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  • 學位論文

反式脂肪酸與阿茲海默症之相關性及其預防

Trans Fatty Acids - Culprits of Alzheimer's Disease and Its Prevention

指導教授 : 何其儻
共同指導教授 : 孫璐西
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摘要


反式脂肪酸(trans fatty acids, TFA)為至少含有一個反式構型雙鍵的不飽和脂肪酸,近來研究顯示體內反式脂肪酸除了來自飲食外,體內之自由基亦會誘導反式脂肪酸生成。阿茲海默症(Alzheimer’s disease, AD)為一種漸進式的神經退化疾病,其發病過程中β-類澱粉胜肽(beta-amyloid peptide, Aβ)會導致體內氧化壓力的上升,故本研究之目的即針對阿茲海默症與反式脂肪酸的相關性進行探討。在化學模式中,以紫外線照射2-氫硫乙醇(2-mercaptoethanol, 2-ME)時,發現反式花生四烯酸(trans arachidonic acid, TAA)會因為含硫自由基攻擊而快速的生成。Myricetin、luteolin與quercetin具有最佳降低含硫自由基誘導TAA生成之活性;反觀sesamol、gallic acid與維生素的活性最低,進而也發現類黃酮物質中具有較高清除含硫自由基活性之重要結構特徵為B環上的3’,4’-dihydroxyl group 與C環上的2, 3-double bond以及4-keto group。在PC-12細胞模式中,發現細胞與2-ME以及H2O2培養後反式脂肪酸會有顯著之上升。無論在預先培養或是共同培養模式中,quercetin、curcumin、resveratrol、retinol acetate、α-tocopherol 與ascorbic acid皆能夠降低細胞內反式脂肪酸之生成,其中又以retinol acetate效果最佳。此外,我們也發現在共同培養模式中quercetin具有增加retinol acetate降低細胞內反式脂肪酸生成之效果。在dextran sodium sulfate (DSS)誘導小鼠大腸發炎之模式與azoxymethane(AOM)誘導大腸發生腫瘤的模式中,大腸黏膜組織內皆未觀察到反式脂肪酸之上升。在老化促進小鼠(Senescence-accelerated mouse prone 8, SAMP8)的模式中,本研究結果顯示12月齡SAMP8小鼠的心臟、脾臟、肺臟、大腦與海馬迴中的反式脂肪酸含量有高於同月齡SAMR1小鼠之趨勢,推測SAMP8小鼠體內反式脂肪酸的上升與AD以及老化造成自由基壓力的累積有關。最後在人類類澱粉前驅蛋白基因轉殖小鼠(human amyloid protein precursor transgenic mice, hAPP mice)的模式中,我們發現6月齡J20基因轉殖小鼠的心臟、腎臟與血球中的反式脂肪酸顯著高於同月齡的B6小鼠,推測J20小鼠體內反式脂肪酸的上升與AD導致自由基壓力的累積有關。

並列摘要


Trans fatty acids (TFA) are unsaturated fatty acids with at least one double bond in the trans-configuration. Some studies have shown that TFA are not only obtained exogenously from food intake, but also generated endogenously by free radicals. Alzheimer’s disease (AD) is a progressive and neurodegenerative disease. Oxidative stress induced by beta-amyloid peptide (Aβ) was considered as a critical component in the pathogenesis of AD. The aim of this study was to investigate the correlation between TFA and AD. In photochemical reaction assay, trans arachidonic acids (TAA) could be effectively generated by thiyl-radicals induced by UV-irradiation of 2-mercaptoethanol (2-ME). Myricetin, luteolin and quercetin had the highest activities in preventing thiyl radical-induced TAA formation, whereas sesamol, gallic acid and vitamins had the lowest. The structures of flavonoids with higher thiyl radical scavenging activities were a 3’, 4’-dihydroxyl group in the B ring and a 2,3-double bond combined with a 4-keto group in the C ring. In the PC-12 cell study, TFA levels in the cells showed a marked increase after treatment with 2-ME and H2O2. The results showed that the elevation of TFAs in PC-12 cells induced by H2O2 and 2-ME could be reduced by quercetin, curcumin, resveratrol, retinol acetate, α-tocopherol and ascorbic acid in both pretreatment and cotreatment experiments. Among the test antioxidants, retinol acetate exhibited the highest activities on reducing TFA formation in PC-12 cells. In addition, we also found that quercetin could enhance the activity of retinol acetate on reducing TFA formation in the cotreatment experiment. In dextran sodium sulfate (DSS)-induced inflammatory bowel disease model and azoxymethane (AOM)-induced colon carcinogenesis model, the results showed that TFA levels in mice colon mucosa did not increase by DSS or AOM treatments. In Senescence-accelerated prone mouse 8 (SAMP8) model, TFA levels in hearts, spleens, lungs, brains and hippocampuses of 12-month-old SAMP8 mice were higher than 12-month-old SAMR1 mice. The elevation of TFA levels might be resulted from the accumulation of free radical stress during pathogenesis of AD and aging. Finally in human amyloid protein precursor (hAPP) transgenic mice model, we found TFA levels in hearts, kidneys, and blood cells of six-month-old J20 mice were significantly higher than six-month-old B6 mice. The elevation of TFA levels might be resulted from the accumulation of free radical stress during pathogenesis of AD.

並列關鍵字

trans fatty acids antioxidants free radicals

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