臺灣博碩士論文加值系統

有許多研究的結果指出糖尿病與阿茲海默症之間有密切的關連，糖尿病是發展成為阿茲海默症之一種高危險因子，兩者可能共享相同的訊息傳遞路徑。於第一型糖尿病(胰島素缺乏)與第二型糖尿病(胰島素阻抗)之糖尿病患者其認知障礙較正常人的差，糖尿病患者體內非酵素性糖化作用的「過度糖化終產物」 (Advanced Glycation End Products，AGEs)含量高於非糖尿病患者，AGEs已被證實與糖尿病之併發症有關。糖尿病治療藥物Thiazolidinediones (簡稱TZDs)，TZDs類藥物是peroxisome proliferators-activated receptors，PPARs的配位子，能夠增加胰島素的敏感性並具有抗發炎等特性。而文獻中阿茲海默症模式動物鼠給予TZDs 類藥物，可以增加其空間認知功能之能力。因此本篇論文主要是探討AGEs加入不同的類神經細胞時，給予TZDs類藥物處理後是否會增加神經細胞的存活能力。本實驗是以MTT方法分析細胞的存活率，結果顯示AGEs加入不同神經細胞時，對PC12細胞株較具有神經毒性，且其毒性反應與AGEs濃度成正相關，抑制50%酵素活性的藥物濃度(IC50)約為4.6 M。若將細胞預先處理Pioglitazone與Rosiglitzaone (TZDs類藥物)後再加入AGEs，實驗結果顯示TZDs藥物可以逆轉AGEs造成的細胞死亡；有趣的是，若使用GSK3抑制劑LiCl前處理細胞後再加入AGEs，亦可以增加細胞的存活率。同時探討PC12細胞株經轉染cdk5與dncdk5質體基因後加入AGEs對細胞存活情形，但此結果與預其結果不同，推測與細胞轉染效率還有PC12細胞內緣性cdk5基因有關。綜合以上結果指出AGEs會直接導致類神經細胞的死亡，並且可以透過前處理TZDs藥物與LiCl藥物來回復，推測AGEs會過度磷酸化Tau蛋白質而造成PC12細胞直接凋亡。
關鍵字：糖尿病、阿茲海默症、過度糖化終產物、Thiazolidinediones

Diabetes mellitus (DM) is one of a chronic disease and there are many research found that DM is associate with Alzheimer’s disease (AD). DM might be a risk factor for AD and both of them might share the same signaling pathway. Type I (insulin deficiency) and Type II (insulin resistance) diabetic patients show impaired cognition. In DM patients non-enzymatic glycation of proteins advanced glycation end products (AGE) level are higher than normal person. AGEs are associated with DM’s complication pathology. Thiazolidinediones (TZDs) drugs are the ligand for peroxisome proliferators-activated receptors (PPARs) and can increase insulin sensitive and anti-inflammation. In the research when give TZDs to AD animal model mice can enhance its space cognition ability. We guess TZDs can improve AGEs to neuron survive. In this study we add AGEs to different neurons, also give TZDs whether increase neurons survival. We use MTT to test the PC12 cell survival rate, when add AGEs the cell toxicity is proportional to cell survival rate. And its IC50 is at 4.6 M. The cell pre-treatment with TZDs drugs Pioglitazone and Rosiglitazone are actually ameliorated by AGEs cell toxicity. And discus the signal pathway further. We also demonstrate the cell pre-treatment with GSK3 inhibitor LiCl can increase the cell survival rate. And using transfection with plasmid cdk5 gene to PC12 cell line adding AGEs for the survival rate expression, one of the groups with mutant cdk5 gene had LiCl, we found that the cell survival rate were higher than AGEs only control. These finding indicated AGEs are actually activing Tau protein hyper-phosphorylated directly causing the neurons apoptosis, and can reverse by TZDs drugs.

中文摘要 Ⅰ
Abstract Ⅱ
目錄 Ⅲ
圖表目錄 Ⅴ
縮寫表 Ⅵ
第一章、緒論 1
第一節、糖尿病 1
第二節、阿茲海默症 4
第三節、過度糖化終產物 7
第四節、糖尿病治療藥物Thiazolidinediones；TZDs類藥物 9
第五節、AGEs所誘發的訊息傳遞途徑 11
第六節、實驗目的 12
第七節、實驗設計 12
第二章、材料與方法 13
第一節、細胞培養 13
第二節、藥物製備 15
第三節、AGEs蛋白質濃度測定 16
第四節、轉形作用 17
第五節、小量質體DNA製備 17
第六節、藥物處理及細胞轉染 18
第七節、MTT細胞存活率分析 18
第八節、細胞蛋白質萃取 19
第九節、西方墨點法 19
第十節、蛋白質Coomassie blue染色 20
第十一節、統計方法 20
第三章、結果 22
第一節、不同糖類與蛋白質BSA共同培養下的糖化作用 22
第二節、AGEs對不同類神經細胞的影響 22
第三節、TZDs與LiCl藥物能減緩AGEs對細胞之傷害 23
第四章、討論 25
第一節、不同糖類之糖化程度差異與生理意義 25
第二節、AGEs對不同神經細胞之影響 26
第三節、糖尿病治療藥物與AGEs 26
第五章、結論與未來展望 29
第六章、圖 30
參考文獻 42

行政院衛生署（2010，12月14日）．九十八年死因統計結果分析．2011年1月1日取自
http://www.doh.gov.tw/CHT2006/DM/DM2_2.aspx?now_fod_list_no=11664&class_no=440&level_no=5九十八年死因結果統計分析
財團法人糖尿病關懷基金會http://www.dmcare.org.tw/
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