臺灣博碩士論文加值系統

阿茲海默症的主要病因是由細胞外amyloid-β (Aβ) 引起的認知障礙和神經元死亡，以及大腦中細胞內的Tau 蛋白聚集，導致其過度磷酸化。大腦中的斑塊主要由一種稱為amyloid-β (Aβ) 的胜肽組成，Aβ會透過形成β-sheet原纖維而聚集。Amyloid-β precursor protein (APP)可以透過三種蛋白水解酶進行剪裁，路徑分別為澱粉樣蛋白途徑和非澱粉樣蛋白途徑。澱粉樣蛋白形成的過程中會被β-secretase和 γ-secretase裂解以釋放β-amyloid peptides及 sAPPβ；非澱粉樣蛋白生成途徑則被 α-secretase裂解，釋放 p3 片段和 sAPPα。 由於ADAM10會透過α-secretase 位點裂解APP，進一步抑制可溶性Aβ 肽的裂解，並生成神經保護性的sAPPα來調節Aβ肽，因此 ADAM10 的分子特性是最重要的生理酵素。本研究使用promoter assay來篩選能夠活化α-secretase並促進非澱粉樣蛋白途徑的藥物候選。結果顯示了兩種藥物候選可以在相對低的EC50值下增加ADAM10表達。在細胞模型中，我使用Western blot分析發現添加化合物L和G化合物有效增加了ADAM10和sAPPα的蛋白質表現。因為Aβ40和Aβ42是阿茲海默症的主要病因，因此想知道這種藥物處理是否能夠有效減少細胞中的Aβ40和Aβ42水平。使用ELISA試劑，發現添加這兩種藥物可以顯著減少Aβ40和Aβ42，表明α-secretase的上調成功將路徑轉移到非澱粉樣蛋白路徑。ADAM10活性試劑顯示這兩種藥物不直接與ADAM10結合，而是增加α-secretase的mRNA和蛋白表達。隨後的RNA序列分析幫助解釋ADAM10活化的機制。這些實驗結果表明這兩種藥物具有改善阿茲海默症的潛力。

Alzheimer's disease is caused by the death of neurons and cognitive impairment resulting from the accumulation of intracellular hyperphosphorylated Tau and extracellular amyloid-β (Aβ) in the brain. The amyloid plaques in the brain primarily consist of a peptide called amyloid-β (Aβ), which aggregates by forming β-sheet fibrils. The amyloid-β precursor protein (APP) can be processed through two proteolytic pathways. The amyloidogenic processing involves cleavage by β- and γ-Secretase, leading to the release of amyloid-β peptides and sAPPβ, while the non-amyloidogenic pathway involves cleavage by α-secretase and -secretase, resulting in the release of p3 fragments and sAPPα. It has been suggested that different metalloproteases may act as potential constitutive α-secretase. ADAM10 cleaves APP through the α-secretase site, inhibiting the production of soluble Aβ peptide and generating neuroprotective sAPPα to regulate Aβ peptide levels. Our study used a ADAM10 promoter assay to screen for potential drugs activating α-secretase and promoting the non-amyloidogenic pathway. The results showed that two drug candidates could enhance ADAM10 expression and increase ADAM10 activity at relatively low EC50 values. In a cell model, I used Western blot analysis to find that adding compounds L and G effectively increased the levels of ADAM10 and sAPPα. Since Aβ40 and Aβ42 are the main culprits in Alzheimer's disease, the researchers wanted to determine if the drug treatment could effectively reduce the levels of Aβ40 and Aβ42 in the cells. Using ELISA kits, we observed that the addition of the two drug candidates significantly decreased the levels of Aβ40 and Aβ42, indicating that the upregulation of α-secretase was successful in shifting the pathway towards the non-amyloidogenic route. The ADAM10 activity assay kit showed that these drugs do not directly bind to ADAM10, but rather increase the mRNA and protein expression of α-secretase. Subsequent RNA sequencing analysis helped elucidate the mechanism of ADAM10 activation. These experiments collectively demonstrate that these drug candidates may help to improve Alzheimer's disease.

摘要 viii
Abstract ix
Acknowledgements xi
Table of contents vi
List of Figures viii
List of Tables ix
Chapter I Introduction 1
1-1 Alzheimer’s disease 1
1-1-1 Basis of molecular progression of Alzheimer's disease 1
1-1-2 Etiology of AD 1
1-1-3 Treatment Strategy 2
1-2 Amyloid Precursor Protein (APP) 3
1-2-1 Trafficking and Proteolytic Processing of APP 3
1-2-2 Proteolytic processing pathway of APP 3
1-3 α-secretase, a disintegrin and metalloprotease 10 (ADAM10) 4
1-3-1 Overview 4
1-3-2 ADAM10 synthesis and structure 6
1-3-3 Regulation of ADAM10 at the translational level 7
1-3-4 ADAM10 in aging and AD 8
1-4 Small molecule drugs for high throughput screening 8
Research aims 12
Chapter II Methods 13
2-1 Plasmid construction, cell culture and plasmid transfection 13
2-2 Promoter assay and cell viability 14
2-3 EC50 16
2-4 Western Blotting 16
2-4-1 Western blot for detecting ADAM10 16
2-4-2 Western blot for detecting sAPPα 17
2-4-3 Western blot for detecting ADAM10 protein 17
2-5 Enzyme-linked immunosorbent assay (ELISA) 18
2-6 ADAM10 protein expression and purification 18
2-7 ADAM10 activity assay 20
2-7-1 Screening ADAM10 enhancer using a purified enzyme. 21
2-7-2 Measuring ADAM10 activity in biological samples. 21
2-8 RNA-sequencing 21
2-8-1 Principal component analysis plot (PCA plot) 22
2-8-2 Volcano plot 22
2-8-3 Heat map 23
2-9 Statistical analysis 23
Chapter III Results 24
3-1 Screening drugs based on increased transcription levels of ADAM10 24
3-1-1 Using ADAM10 promoter assay for drug screening 24
3-1-2 Cell viability 25
3-1-3 EC50 of promoter assay 25
3-2 Compound efficiently enhanced translation in a cellular model 26
3-2-1 Enhanced ADAM10 translation in a cellular model 26
3-2-2 Enhanced sAPPα secretion in a cellular model 28
3-3 Small molecule drugs promote the reduction of Aβ 29
3-3-1 ELISA kit of Aβ40 29
3-3-2 ELISA kit of Aβ42 30
3-4 Protein expression and purification 31
3-5 Drugs increase ADAM10 activity 32
3-6 Interaction between drugs and ADAM10 33
3-7 RNA-sequencing for drug detection 34
Chapter IV Discussion 37
Figures 43
References 67
Appendix A: Materials 73
Appendix B: negative control 77

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