茶多酚對於阿茲海默症及代謝症候群預防機制之研究

茶是世界上最被廣泛飲用的飲料，而其中許多的成分，特別是多酚類化合物在流行病學上被證實可以降低許多疾病的風險。在本研究中，我們據此來探討茶多酚對於阿茲海默症及代謝症候群的預防作用機制。在第一部份中，本研究發現處理EGCG可以經由促進類澱粉蛋白的分解機制，使得神經細胞中的類澱粉蛋白含量得以有效的降低，進一步發現除了這個機制外，EGCG更可以透過抑制細胞中c-Abl蛋白激酶的活性來達到保護神經細胞的效果。在第二部分中，已知在第二型糖尿病中高血糖的症狀會造成體內胰島素信息傳遞的衰減，因此利用高糖處理肝細胞的實驗模式提出一個可能的EGCG抗糖尿病機制。本研究發現高糖會促使肝細胞中IRS蛋白活性下降，進一步使得由胰島素促進的Akt蛋白磷酸化受到抑制，然而處理EGCG可以回復IRS蛋白的活性，並使得胰島素信息傳遞受到抑制的情形得以緩解。在第三部分中，探討為何茶多酚對於肝細胞具有顯著抑制脂質累積的能力。本研究發現茶黃素多酚類對於降低肝細胞中脂質的累積與合成具有顯著的效果，進一步證實此種抑制作用主要是透過調控活性氧自由基與LKB-1蛋白激酶，來誘導AMPK蛋白激酶活性增加，使得合成脂質的關鍵酶ACC的活性得以被抑制。綜合以上的研究結果證明茶多酚對於抑制由類澱粉蛋白導致的阿茲海默症與抗糖尿病等皆能發揮其顯著功效，希望經由發現這些機制在未來對於這些疾病的預防與治療上能有所貢獻。

關鍵字

茶多酚；阿茲海默症；乙型類澱粉；胰島素；代謝症候群

並列摘要

Tea is the most consumed drink in the world containing many compounds particularly polyphenols shown to reduce the risk of a variety of diseases in epidemiological studies. In the present study, we demonstrated the possible preventive mechanisms of tea polyphenols on Alzheimer's disease and metabolic syndrome model. In part I, the results deminstrated that treatment with EGCG reduced the Aβ levels by enhancing endogenous APP nonamyloidogenic proteolytic processing in Aβ-induced AD model both in vitro and in vivo. Moreover, our results indicated that the neuroprotective action of EGCG may take place through c-Abl inhibition other than the promotion of APP nonamyloidogenic proteolysis. Part II demonstrated a possible mechanism for the antidiabetic effects of EGCG. As insulin resistance is a primary characteristic of type 2 diabetes resulting from hyperglycemia defects in insulin signals transduction, the aim of this study was to investigate the effects of EGCG on the insulin signaling pathway under high glucose. The results showed that high glucose downregulates IRS signaling activity, and subsequently repress hepatic glucose uptake and utilization by suppressing Akt activity. However, the EGCG supplementation alleviates this insulin signaling blockade by improving the function of IRS molecules, establishing a new molecular mechanism for antidiabetic activities of tea. In part III, the study examined why tea polyphenols have inhibitory effects on liver fat accumulation of hepatic cells. The results demonstrated that the tea compounds theaflavins significantly reduced hepatic lipid content, suppressed fatty acid synthesis both in vitro and in vivo. Furthermore, theaflavins also inhibited ACC activities by stimulating AMPK through LKB-1 and ROS pathway. The above-listed observations reveal that tea polyphenols indeed inhibit Aβ-induced neurotoxicity and display some antidiabetic benefits. Our results suggest that tea polyphenols show protection effects in the target cells and may be useful for the prevention of these diseases.

並列關鍵字

tea polyphenol ； beta-amyloid ； insulin ； metabolic syndrome

參考文獻

General Introduction

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[3] Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Chemoprevention of pancreatic cancer: a review of the molecular pathways involved, and evidence for the potential for chemoprevention. Pancreatology 2006;6(5):429-39.

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茶多酚對於阿茲海默症及代謝症候群預防機制之研究

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