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研究生:陳暐婷
研究生(外文):Wei-Ting Chen
論文名稱:臺灣家族性阿茲默症基因突變的致病機轉
論文名稱(外文):Pathogenic Mechanisms of Familial Alzheimer's Disease: Amyloid Precursor Protein D678H mutation and Presenilin-1 G206D mutation in Taiwanese pedigrees
指導教授:鄭菡若
指導教授(外文):Irene Han-Juo Cheng
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:103
語文別:英文
論文頁數:96
中文關鍵詞:阿滋海默症突變類蛋粉蛋白前驅物鈣離子
外文關鍵詞:Alzheimer's DiseasemutationAmyloid precursor proteincalciumpresenilin-1
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隨著醫學進步,人類平均壽命延長,慢性疾病逐漸成為現代公共衛生的重要議題。阿滋海默症為老年失智人口最主要族群,去年全球失智人口總數約為四千五百萬,阿滋海默症約佔失智總人口百分之七十五。隨著老年人口急劇增加,阿滋海默症帶來的社會負擔將不容小覷。

目前仍未有生物指標可精確診斷疾病進程,也沒有治療方法可將疾病治癒。增加對疾病的認識以減緩阿滋海默症即將帶來的衝擊,乃現今各國研究的重要方針。類澱粉蛋白異常堆疊是目前阿滋海默症的主要致病假說,然而近二十年來針對類澱粉蛋白的治療皆未能通過臨床試驗。本論文僅針對在台灣家族中找到的兩個導致早發型家族阿茲海默症的突變進行研究,以探討任何可能導致阿滋海默症的相關病理機轉,希望能藉此對未來研究方向有所幫助。

關於類澱粉前驅蛋白D678H突變,我們發現它不正常增加類澱粉蛋白的產生、聚集以及細胞毒性,並增加與金屬離子的螯合及寡倍體的產生。此研究再次驗證類澱粉蛋白的重要性,同時首次為金屬離子螯合劑應用在治療上提供基因佐證。關於presenilin-1 G206D突變,我們發現它不正常增加具毒性類澱粉蛋白的比例,並進一步使內質網中鈣離子濃度異常升高,然而在溶酶體中鈣離子濃度未受明顯影響且自噬小體也能正常代謝。此外,G206D降低presenilin與Pen2親和度、蛋白質穩定性以及在內質網的表現量。此研究除再度証實類澱粉蛋白重要性,也指出探討內質網的鈣離子調控將對疾病的致病機轉有助益。最後,在眾多阿滋海默症的相關致病機轉中,彼此一直缺乏連結性。我們的研究也指出蛋白質在細胞中的座落位置是決定其功能性的關鍵,可用來暗示不同的病理現象。因此,探討類澱粉前驅蛋白或是presenilin中負責調控蛋白質在細胞間運輸的氨基酸將對疾病的致病機轉有助益。 

Alzheimer’s disease (AD), the most common form of dementia, has a worldwide prevalence over 5% in people age 65 and older. There is no cure for the disease, which results in a heavy social burden. Around 0.1% of the AD cases are early-onset (before age 65) familial forms of the autosomal dominant inheritance, attributed to mutations in one of the three genes: those encoding amyloid precursor protein (APP), and presenilin-1 (PS1) and -2 (PS2). Genetic predisposition provides a powerful tool to reveal the pathogenic mechanisms of the disease.

Our group characterizes pathogenic mechanisms of two mutations, encoding APPD678H and PS1G206D mutants, found in Taiwanese pedigrees. One of the pathogenic hallmarks of the disease is the amyloid plaque, in which abnormal concentrated amyloid beta (Aβ) peptide and metal ions deposit. Aβ peptide, product of APP cleaved by γ-secretase, is currently considered to be the major trigger of the disease. PS1 is the catalytic component of the γ-secretase complex and Pen2 is a critical co-factor for γ-secretase activity.

APPD678H has an additional metal ion-coordinating residue, histidine (H). We speculate that this mutation may promote susceptibility of Aβ to ions. We found that the D678H mutation increases Aβ production and prolonged Aβ oligomer state with higher neurotoxicity. D678H also increases Aβ susceptibility to zinc and copper, which lead to altered aggregation pathway. Therefore, our study not only characterizes the D678H mutant Aβ aggregation pathway in detail, but also first time provides a genetic evidence for the importance of zinc and copper in the disease.

PS1G206D provides an additional polar transmembrane-based amino acid, aspartate (D), near the Pen2 binding site. We speculate that this mutation may interfere with the Pen2 binding and PS1 functions. We found that the G206D mutation decreases PS1-Pen2 interaction, but does not abolish γ-secretase activity. For γ-secretase dependent function, the G206D mutation alters the proportion of Aβ varieties, but does not alter Notch cleavage. For γ-secretase independent function, this mutation disrupts the calcium homeostasis but not endo-lysosomal functions. Therefore, our study not only characterizes the general functions of PS1 G206D mutant in detail, but also fir the first time provides genetic evidence for the importance of PS1-Pen2 interaction in the disease.

Together, genetic tool helps us to dissect the pathogenic mechanism in cellular models and that could further provide therapeutic target for the disease. We highlight the importance of Aβ-ions and PS1-Pen2 interaction in AD pathology.


Contents
Acknowledgment (Chinese)--- i
Abstract (Chinese)-------------- ii
Abstract (English)----------- iii
Publications and Presentations----- iv
List of Abbreviations----------- vii
List of Figures------------------ ix

Chapter 1. General Introduction------------------------ 1

1.1 Alzheimer’s disease (AD)………………………………… 2
Prevalence
Pathologic Hallmark
Genetics
1.2 Familial Alzheimer’s disease (FAD).………. 3
Amyloid Precursor Protein (APP)
Presenilin (PS)
Mechanism
1.3 Medications for Alzheimer’s disease…………….. 6
Current options
Anti-amyloid strategy
Aβ-directed immunotherapy to promote amyloid clearance
Targeting β-secretase or γ-secretase to reduce Aβ production
Challenges for clinical trials
Prevention for AD
1.4 Motivation and Goal……………………………… 10

Chapter 2. Amyloid Precursor Protein (APP) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-Zinc/Copper Assemblies---------- 12

2.1 Introduction…………………………………………… 13
Localization of APP mutations
Aβ aggregation
Metal ions in Alzheimer’s disease
Aβ-metal interaction
APP D678H mutation
2.2 Method………………………………………………… 16
Human subject
Materials
Plasmids
Cell culture
APP and Aβ measurement
Aβ preparation
Photo-induced cross-linking of unmodified proteins (PICUP)
ThT assay
MTT assay
Transmission Electron Microscopy (TEM)
Ion titration and BisANS fluorescence
Metal reduction assay
1.3 Result………………………………………………… 21
Clinical Description and Genetic analysis
D678H Enhances Amyloidogenic Cleavage and Increases the Aβ42/40
D678H Switches the Aβ Aggregation Process
D678H Promotes Aβ42 Neurotoxicity
D678H Alters the Biochemical Features of Ion-induced Aβ Assemblies
D678H Promotes the Interaction of Zn2+ and Cu2+ With Aβ
D678H Has Lower Redox Activity
2.4 Discussion……………………………………… 36
Effect of Intra-Aβ Mutations on APP Processing and Sorting
Role of the Aβ N-terminal Region in Toxicity and Aggregation
Effect of Metal Ions on Aβ Aggregation
Redox Activity of Aβ
2.5 Conclusion………………………………………… 41

Chapter 3. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca2+ Accumulation----------------------42

3.1 Introduction………………………………………… 43
Localization of PS1 mutations
Presenilin and γ-Secretase
PS1 Function Independent of γ-Secretase Activity
Discovery of the PS1 G206D Mutation
3.2 Method………………………………………………………………… 46
Cell Culture
Plasmids
Immunoprecipitation (IP) Analysis
Gel Electrophoresis and Western Blotting Analysis
Cellular Organelle Fractionation
Immunocytochemistry
Enzyme-Linked Immunosorbent Assay (ELISA)
Fura-2-AM Ca2+ Imaging Experiments
Autophagy Assay
Apo-BrdU-RedTM In situ BrdU (TUNEL) labeling assay
Propidium Iodide Staining for Cell Cycle Analysis
Flow Cytometry
3.3 Result………………………………………………………………… 52
G206D Reduces PS1-Pen2 Interaction But Not γ-Secretase Activation
G206D Increases the Production of Aβ42 But Not NICD
G206D Disrupts the ER Ca2+ Homeostasis
G206D Alters PS1 Localization in ER and Early Endosome
G206D Did Not Affect Lysosomal Calcium and Autophagy
G206D Did Not Affect Cell Death Rate Under Oxidative Stress
3.4 Discussion………………………………………………………………… 64
Effects of the G206D mutation on γ-secretase formation and activity
G206D mutation increased ER Ca2+ storage but not lysosomal function
Subcellular distribution of PS1 altered by the G206D mutation
G206D mutation did not alter cell survival under oxidative stress
Calcium dysregulation as a driver for AD pathology
3.5 Conclusion………………………………………………………………… 70

Chapter 4. General Discussion and Conclusion--------- 71

4.1 General Discussion………………………………………………………… 72
Sporadic Alzheimer’s disease
What’s going on in the world
Taiwan Biobank
Implications from our studies
4.2 Conclusion……………………………………………………….………… 78

References------------------------- 80



List of Figures
Chapter 1
Figure 1-1. Challenge of super-aged society and dementia population in Taiwan……………….2
Figure 1-2. APP processing via two alternative pathways…………………………...……………..4
Figure 1-3. Sequential processing of C99 by γ-secretase releases Aβ products………..…………..5
Figure 1-4. Amyloid cascade………………………………………………………………………….11

Chapter 2
Figure 2-1. APP mutations linked to Alzheimer’s disease………………………..………….……..13
Figure 2-2. Aβ self-assembly………………….………………………………………………………14
Figure 2-3. A schematic energy landscape for protein folding and aggregation.…………………14
Figure 2-4. Model of Aβ coordinated to zinc or copper.…………………………………………….15
Figure 2-5. Pedigree and clinical data identify a novel familial Alzheimer’s disease mutation at
Aβ N-terminus……………………………………………………………………………23
Figure 2-6. D678H mutation enhances amyloidogenic pathway and increases extracellular
Aβ42/40 ratio………..……………………………………………………………………25
Figure 2-7. D678H mutation did not alter intracellular Aβ level..…………………………………26
Figure 2-8. Transfect efficiency and APP maturity of APPwt and APPD678H in HEK293T cell….26
Figure 2-9. D678H mutation promotes Aβ40 HMW but Aβ42 LMW assembly formation………28
Figure 2-10. Aβ morphology in the presence or absence of metal ions was revealed by TEM…...29
Figure 2-11. Different Aβ preparations also confirmed that the D678H mutation promotes Aβ40
HMW but Aβ42 LMW assemblies formation.…..…………………………………….30
Figure 2-12. D678H mutation enhances the neurotoxicity of Aβ42…………………………...……31
Figure 2-13. D678H mutation shifts Zn2+ and Cu2+-induced assemblies toward smaller oligomers
with fewer fibrils. ……………..…………..……….……………………………………33
Figure 2-14. D678H mutation promotes the binding of Zn2+ and Cu2+ to Aβ……………………35
Figure 2-15. The representative emission spectra of BisANS………………………………..…..…35
Figure 2-16. D678H mutation decreases the redox activity of Aβ42 in metal reduction assay...36
Figure 2-17. The effect of Aβ-N-terminal mutations on amyloidogenic cleavage…………………37

Chapter 3
Figure 3-1. Presenilin mutations linked to Alzheimer disease……………………………………...43
Figure 3-2. γ-Secretase complex..……………………………………………………………………..44
Figure 3-3. GFP-tagged PS1 variants were endoproteo- lytically processed………………………47
Figure 3-4. G206D mutation reduced PS1-Pen2 interaction but not PS1 endoproteolysis……….53
Figure 3-5. G206D mutation increased Aβ42 ratio but not NICD levels….………………...………55
Figure 3-6. G206D mutation increased ER Ca2+ storage.……………...………………...…………57
Figure 3-7. G206D mutation decreased PS1 levels in ER but increased PS1 levels in early
endosome.….......………………...……...………………...……...………………...…..…59
Figure 3-8. G206D mutation did not alter protein stability………………...……...……….………60
Figure 3-9. G206D mutation did not affect autophagosome maturation and lysosomal Ca2+
storage…….………...……...……….……………...……...……….……………...……..61
Figure 3-10. G206D mutation did not alter survival response under oxidative stress……………63
Figure 3-11. PS1 function independent of γ-secretase…...……………..……...……….…...………66
Figure 3-12. Model of the polar interface in TMD4PS1 and assigned function of polar amino
acids…………….……………..……...……….…...……………..……...……….…...…67

Chapter 4
Figure 4-1. The graph depicts the biomarkers as indicators of Alzheimer’s disease..……..……..74
Figure 4-2. Models of zinc and copper in the glutamatergic synapse in health and Alzheimer’s
disease...……….…...……………..…….......……….…...……………..……...……….…75
Figure 4-3. Role of STIM2-nSOC-CaMKII Pathway in Maintenance of Mushroom Postsynaptic
Spines..…...……….………….…...…………….…...………...……….…...……………..76
Figure 4-4. Schematic representation of PS1FAD mutations analyzed in ER calcium leak function
experiments.….…...…………….…...….…...…………….…...………….…...…………78



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