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研究生: 王秀觀
Hsiu-Kuan Wang
論文名稱: 台灣人族群阿茲海默氏症及血管型失智症的生物標記評估
Estimation of biomarker candidates for Alzheimer’s disease and/or vascular dementia in Taiwanese population
指導教授: 李桂楨
Lee, Guey-Jen
學位類別: 博士
Doctor
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2009
畢業學年度: 97
語文別: 英文
論文頁數: 106
中文關鍵詞: 阿茲海默症血管型失智症遺傳變異疾病相關性基因表現分析
英文關鍵詞: Alzheimer’s disease, vascular dementia, genetic variation, disease association, expression analysis
論文種類: 學術論文
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  • 阿茲海默症與血管型失智症是最普遍的兩類失智症。目前有關阿茲海默症的疾病診斷生物標記分子研究中,已知的遺傳標記分子有脂蛋白E基因4對偶基因、類澱粉蛋白前驅蛋白基因突變、早老素1及早老素2基因突變等。腦部及腦脊髓液中tau蛋白與類澱粉蛋白含量則為已確認的阿茲海默症疾病診斷蛋白標記分子。本研究利用台灣阿茲海默症、血管型失智症與正常人族群基因分型技術,分析候選基因多型性變異與疾病的相關性。結果發現脂蛋白E基因4對偶基因是阿茲海默症、而非血管型失智症的風險因子;血管收縮素轉換酶基因DD基因型、D對偶基因和-240 T – Alu D單套型是阿茲海默症與血管型失智症的風險因子;此外,實驗結果顯示介白素1基因-889 CT基因型對於70歲以上的血管型失智症罹病感受方面具有潛在的保護功能;同時,熱休克A5基因-415 AA/-180 GG基因型、-415 A/-180 G對偶基因會減低罹患阿茲海默症的風險。基因表現分析結果亦顯示,具有-415 A/-180 G對偶基因的細胞在遭受內質網壓力之後,其熱休克A5蛋白被誘發產生的程度明顯增加。由於尋找阿茲海默症淋巴細胞的生物標記的可行性,本論文亦分析了8個阿茲海默症及4個年齡、性別配合之正常人的APP蛋白型式及氧化蛋白,但未找到明顯的蛋白標記。以上實驗結果顯示,上述與阿茲海默症及/或血管型失智症的罹病相關的基因,可作為協助疾病診斷的遺傳標記分子。

    Alzheimer’s disease (AD) and vascular dementia (VaD) are the most prevalent forms of dementia. To date, the allelic variants of apolipoprotein E (APOE), genetic mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes, the levels of tau proteins and amyloid beta-peptides in brain and cerebrospinal fluid (CSF) are the well-documented biomarkers for AD. In the study, AD patients, VaD patients and ethnic-matched nondemented controls were analyzed by means of genotype association method. APOE 4 allele acts as risk factors only for Taiwanese AD, not for VaD. Angiotensin I-converting enzyme (ACE) DD genotype, ACE D allele and ACE -240 T – Alu D haplotype are risk factors for both AD and VaD. Besides, the results suggest a potential protective role of IL-1 -889 CT genotype in VaD susceptibility among Taiwanese over 70 years. Also a decrease in risk of developing AD for HSPA5 -415 AA/-180 GG genotype and HSPA5-415 A/-180 G allele was found. Expression analysis revealed that induction of HSPA5 expression after ER stress was markedly increased in the cells with the -415 A/-180 G allele. Since finding biomarkers in lymphocytes for AD is feasible, lymphoblastoid cells from 8 AD patients and 4 age-gender matched controls were used to study different APP forms and oxidized proteins associated with AD. However, no apparent protein marker was identified. Thus, the data suggested that genes involved in the prevalence of AD and/or VaD and may act as the genetic biomarkers for dementia diagnosis.

    Index Index I 摘要 IV Abstract V List of tables and figures VI Introduction 1 Alzheimer’s disease and vascular dementia 1 AD/VaD diagnostic biomarkers 1 Apolipoprotein E 2 Angiotensin I-converting enzyme 3 Tissue kallikrein 1 4 Interleukin-1α and interleukin-1β 4 HSPA5 chaperone 5 Protein candidate markers for Alzheimer’s disease 7 Amyloid precursor protein forms ratio as biomarker for AD 7 Oxidation-sensitive protein as biomarker for AD 9 Specific Aims 12 Aim 1. To identify probable genetic factors for AD and VaD 12 Aim 2. To identify protein biomarkers from transformed lymphoblasts from AD patients and controls 12 Materials and methods 13 I. Case-control study to identify genetic risk markers for dementia 13 Subjects 13 Genomic DNA extraction 14 Polymerase chain reaction (PCR) and genotyping 14 Statistical analysis 15 II. ACE promoter -240 A/T and Alu I/D reporter functional assay 16 Promoter constructs 16 (A) ACE-firefly/TK-Renilla dual luciferase reporter constructs 16 (B) ACE-firefly luciferase - Alu I/D reporter constructs (pGL3-ACE-A/T-I/D) 17 Preparation of electro-competent cells 17 Ligation 18 Electroporation 18 Minipreparation of plasmid DNA 18 Midipreparation of plasmid DNA 19 Cell cultivation 20 Promoter functional assay and statistical analysis 20 III. HSPA5 promoter SNPs and ER stress functional assay 21 Lymphoblastoid cell cultivation 21 RNA isolation 21 Real-time quantitative RT-PCR analysis of HSPA5 expression 22 IV. Western blot analysis of APP forms ratio 22 Cell lysate preparation 22 Western blotting and statistical analysis 23 V. Western blot analysis of oxidation-sensitive protein 24 Preparation of DNPH-derivatized proteins 24 Carbonyl immunreactivity assay and statistical analysis 24 Results 26 I. Case-control study to identify genetic risk markers for dementia 26 APOE, ACE and KLK1 gene polymorphisms and the risk of dementia 26 IL-1α and IL-1β gene promoter polymorphism and the risk of dementia 27 HSPA5 gene promoter polymorphism and the risk of dementia 28 II. ACE promoter functional study 30 ACE-firefly/TK-Renilla dual luciferase reporter constructs and assay 30 ACE-firefly luciferase - Alu I/D reporter constructs and assay 30 III. ER stress and HSPA5 expression study 31 IV. APP forms ratio study 31 V. Oxidation-modified protein study 32 Discussion 33 APOE, ACE and KLK1 gene polymorphisms and the risk of dementia 33 IL-1α and IL-1β gene promoter polymorphisms and the risk of dementia 36 HSPA5gene promoter polymorphism and the risk of dementia 38 APP forms ratio study 40 Oxidation-modified protein study 42 Conclusions 45 References 46 Legends for tables and figures 72

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