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研究生：	吳柏帆 Wu, Po-fan
論文名稱：	以弱化USP48 基因表現為阿茲海默症新穎治療策略之轉譯醫學研究 The translational study to determine the therapeutic potential of USP48 knockdown for Alzheimer’s disease
指導教授：	廖永豐 Liao, Yung-Feng
共同指導教授:	呂佩融 Lu, Pei-Jung
學位類別：	博士 Doctor
系所名稱：	醫學院 - 跨領域神經科學國際博士學位學程 TIGP on The Interdisciplinary Neuroscience
論文出版年：	2022
畢業學年度：	110
語文別：	英文
論文頁數：	78
中文關鍵詞：	阿茲海默症、β 類澱粉蛋白、類澱粉前驅蛋白、第 48 型泛素特異性蛋白酶
外文關鍵詞：	Alzheimer's disease, Amyloid-β peptide, Amyloid precursor protein, Ubiquitin-specific peptidases 48
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阿茲海默症主要是由β類澱粉蛋白（Amyloid-β）在病人腦部堆積，導致認知功能退化的一種神經退化性疾病。很不幸的是，目前還沒有能有效抑制β類澱粉蛋白神經毒性所造成的神經退化。類澱粉蛋白是由一系列蛋白酶切割類澱粉前驅蛋白 (Amyloid Precursor Protein，簡稱APP) 所產生，並且也是阿茲海默症病人腦部的老年斑塊中主要的蛋白質成分。雖然之前有研究證明APP 可以被泛素 E3 接合酶標記並引導其降解，但很少有研究探討 APP 的降解是否會受到泛素特異性蛋白酶（ubiquin-specific peptidases，簡稱USPs）調控。之前研究發現泛素特異性蛋白酶的其中一個成員第48型泛素特異性蛋白酶（USP48）的mRNA 在阿茲海默症病人的海馬迴當中表現量比正常人還多。因此我們想了解，改變USP48的表現量是否能改變APP 蛋白質的降解速率並進而影響Amyloid-β 的產量。利用有表現黃色螢光蛋白標記的 APP 細胞，我們發現到當細胞過量表現 USP48時，確實會增加 APP 蛋白質的穩定性，同時增加Amyloid-β的產量。當使用RNA干擾術降低細胞中 USP48的表現量時，則能增強APP 蛋白質被溶酶體裂解的機會，從而減少APP 蛋白的恆定量及Amyloid-β的產量。我們進一步利用阿茲海默症模式轉殖小鼠，以腺病毒載體將USP48的RNA干擾序列送入小鼠的海馬迴腦區，誘發USP48在海馬迴的表現量明顯下降並維持兩個月。結果我們發現，減量表現海馬迴的USP48後，可以顯著增強阿茲海默症轉殖小鼠的學習認知功能，並降低其腦部類澱粉斑塊的堆積量。綜合這些實驗結果，我們證明了USP48具有調節神經系統中APP 蛋白恆定量的全新功能，並驗證可以經由控制USP48此一全新功能達到調控Amyloid-β的產量。這項研究也提供強而有力的理論基礎，可繼續開發USP48標定的阿茲海默症新穎療法。

The main symptom of Alzheimer’s disease (AD) is a chronic and progressive decline in cognitive function. Unfortunately, the available AD treatments are not curative, and there is no way to halt the progression of cognitive impairment. The primary cause of AD pathogenesis is thought to be amyloid-β (Aβ) peptides, which are generated by the amyloidogenic proteolysis of amyloid precursor protein (APP) and are the main constituents of amyloid plaques. Although many studies have focused on the function of ubiquitin E3 ligases in regulating APP stability, few have investigated how deubiquitinases might contribute to APP homeostasis. Nevertheless, previous studies have demonstrated that the mRNA expression of ubiquitin-specific peptidase 48 (USP48; a member of the ubiquitin-specific peptidase family) is increased in the hippocampus of AD patients. We thus sought to determine if altered USP48 levels might affect the production of Aβ by affecting APP proteostasis. Using a HEK-derived cell line that constitutively expresses yellow fluorescent protein-tagged APP (APP-YFP), we demonstrated that RNA interference-mediated downregulation of USP48 expression enhances lysosomal degradation of APP, leading to a marked reduction of the full-length protein and secreted Aβs. Consistently, we further found that overexpression of USP48 enhances APP protein stability and concomitantly increases the level of secreted Aβ. Finally, we validated the efficacy of USP48 knockdown in vivo using APP/PS1 transgenic mice, finding that downregulation of USP48 in the hippocampus of APP/PS1 mice can diminish the amyloid plaque load and significantly improve cognitive function. Together, our findings suggest that USP48 plays a pivotal role in governing the proteostasis of APP by modulating lysosomal degradation of APP. This study expands the known molecular repertoire that contributes to Aβ homeostasis in the central nervous system and suggests that USP48 might be a valuable therapeutic target for AD.

Abstract i 
Acknowledgments v 
Table of contents vii 
List of figures xi 
Abbreviations xiii 
Chapter 1: Introduction 1
1.	Alzheimer's disease and APP degradation 1
2.	Ubiquitin-specific peptidases and Alzheimer's disease 2
3.	Ubiquitin-specific peptidase 48 3
Chapter 2: Significance of study and objectives 5
Chapter 3: Materials and methods 7
1. Reagents 7
2. Plasmid DNA 7
3. Cell culture and transfection 8
4. Primary cortical neuron culture 9
5. Preparation of lentiviral stocks 9
6. Western blotting 10
7. Aβ40 and Aβ42 ELISA 11
8. Measurements of sAPPα and sAPPβ levels 11
9. Measurement of APP turnover 12
10. In vitro deubiquitination assays 12
11. APP ubiquitination assays 13
12. Immunofluorescence staining and microscopy 13
13. LysoTracker live-cell imaging 14
14. CatD enzyme activity assay 15
15. Confocal imaging of autophagosome/autolysosome 16
16. Animal handling 16
17. Stereotaxic surgery 17
18. Morris water maze 17
19. Y-maze 18
20. Immunohistochemistry (IHC) 18
21. X-34 plaque staining 19
22. Statistics 19
Chapter 4: Results 20
1. USP48 increases APP protein and Aβ production in APP-YFP cells 20
2. Downregulation of USP48 decreases APP protein and Aβ production in APP-YFP-expressing cells 23
3. USP48 does not alter γ-secretase activity in C99-CFP-expressing cells 25
4. USP48 increases β-secretase expression but does not alter the levels of α- or γ-secretases 26
5. USP48 stabilizes APP protein by reducing APP degradation 29
6. USP48 does not deconjugate ubiquitin from APP 30
7. USP48 knockdown decreases APP-YFP by lysosomal degradation 32
8. USP48 increases intracellular vesicular APP in APP-YFP cells 33
9. Knockdown of USP48 reduces endosomal APP by enhancing lysosomal degradation 35
10. USP48 reduces numbers of acidic lysosomes and CatD enzyme activity 37
11. USP48 overexpression impairs autophagic flux and reduces lysosomal protein expression 41
12. Knockdown of USP48 in rat primary cortical neurons decreases APP level and production of Aβ and sAPPs 46
13. USP48 knockdown in the hippocampus improves short-term and long-term spatial memory in APP/PS1 transgenic mice 47
14. USP48 knockdown in APP-PS1 mouse hippocampus reduces amyloid plaque load 51
Chapter 5: Discussion 55 
Chapter 6: Conclusions 63 
Chapter 7: References 65 
Chapter 8: Appendix 78
                                    

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