醣化蛋白終極產物在 SH-SY5Y 神經瘤細胞株中對 SIRT1 及相關路徑影響之研究

The effect of Advanced Glycation End products on SIRT1 and relative pathway in SH-SY5Y cells

邱國雄(Kou-Hsiung Chiu)

指導教授 ： 柯順耀

長榮大學/健康科學學院/生物科技學系(所)/碩士(2015年)

https://doi.org/10.6833/CJCU.2015.00056

摘要

目前為止全球約有三千萬人罹患阿滋海默症 (Alzheimer’s disease； AD)，阿滋海默症是一個不可逆的神經退化性疾病，其治療及致病機制尚未完全清楚，近年來許多研究指出，有著長壽基因之稱的 SIRT1 基因可以延長細胞壽命，保護細胞免於老化的功能，對於阿滋海默症的相關機制上可能是個重要的關鍵。本實驗室先前研究發現，在 SH-SY5Y 細胞中醣化蛋白終極產物 (Advanced Glycation End Products ；AGEs) 藉由活性氧化物 (Reactive oxygen species； ROS) 刺激細胞中β-類澱粉蛋白 (amyloid β； Aβ) 的表現，進而造成神經細胞死亡。為了更進一步釐清 AGEs 在阿滋海默症中的相關調控機制，本論文將探討 AGEs 和 SIRT1 之間的相互關係，研究 AGEs 對於 SIRT1 之相關下游調控及其相互之關係。結果顯示 AGEs 藉由 ROS 刺激 SIRT1 及 p53 的表現，同時提升了凋亡相關因子 Bax/ Bcl-2 比率及 caspase 3 的表現，此外也發現 AGEs 提升了細胞內質網壓力蛋白指標 GRP78 的表現。有趣的是， AGEs 及白藜蘆醇 (Resveratrol) 同時處理細胞時之結果與以 AGEs 單獨處理細胞後有所不同，隨著時間變化 SIRT1 及相關受調控之蛋白和 ROS 的減少呈現正相關的關係，此暗示著，在 AGEs 存在之情況下 SIRT1 的表現可能是調控細胞走向凋亡的重要原因，而並非所有時候都能夠保護細胞免於凋亡。

關鍵字

阿茲海默症 ； 醣化蛋白終極產物 ； 活性氧化物 ； β-類澱粉蛋 ； 白藜蘆 醇

並列摘要

So far, about thirty million people suffer from Alzheimer's disease (AD) in worldwide. The treatment and pathogenic mechanisms of AD are not yet fully understood. In recent years, many studies have suggested that silent information regulator 1 (SIRT1) gene could prolong the life of cells and protect cells from aging. SIRT1 may play an important role in AD. Previous studies in our laboratory found that Advanced Glycation End Products (AGEs) could increase the expression of amyloid β (Aβ) via Reactive oxygen species (ROS) and caused cells death in SH-SY5Y. In order to further clarify the AGEs related regulatory mechanism in AD. This thesis will explore the relationship between AGEs and SIRT1, and research the related downstream regulation of their mutual relations. The results show that SIRT1 and p53 are stimulated by AGEs via ROS, while inducing the apoptosis-related factors Bax / Bcl-2 ratio and increasing caspase-3 expression. Furthermore, AGEs enhance the endoplasmic reticulum stress protein GRP78. Interestingly, there have very different results of AGEs and resveratrol simultaneously treat the cells. The expression of SIRT1 and related proteins are decreased by the reduction of ROS with different times, and shows a positive correlation. This implies that SIRT1 may be an important role in regulating cell apoptosis in the situation of treatment with AGEs, and not at all times able to protect cells
from apoptosis.

並列關鍵字

Advanced Glycation End Products ； Reactive oxygen species ； amyloid β ； resveratrol ； silent information regulator 1

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