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系統識別號 U0026-1507201523211300
論文名稱(中文) 高血壓在3xTg小鼠及豬隻動物上增加濤蛋白磷酸化與乙型類澱粉蛋白的產生
論文名稱(英文) Hypertension increases tau hyperphosphorylation and Aβ production in 3xTg mice and pigs
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 施耀翔
研究生(英文) Yao-Hsiang Shih
電子信箱 owenaaaaaa@hotmail.com
學號 S58981507
學位類別 博士
語文別 英文
論文頁數 72頁
口試委員 指導教授-郭余民
召集委員-江美治
口試委員-司君一
口試委員-許桂森
口試委員-林靜茹
口試委員-陳韻如
中文關鍵字 高血壓  阿茲海默氏症  海馬回  學習記憶  乙型類澱粉蛋白  Tau蛋白 
英文關鍵字 hypertension  hippocampus  learning and memory    Tau 
學科別分類
中文摘要 研究背景: 過去研究指出,高血壓與神經退化疾病、認知障礙有關,特別是中年高血壓會增加晚年罹患阿茲海默症的風險。然而,高血壓是否會導致阿茲海默症,或者此二者只是老化的共病現象,目前仍不清楚。
研究目的: 高血壓與阿茲海默症之間是否存在著因果關係。
實驗方法: 本研究以小鼠和豬兩種不同的動物模式,研究高血壓與阿茲海默症的關係。第一種動物模式,係在2、5及7個月大的阿茲海默症基因轉殖小鼠(帶有APPswe、PS1M146V及TauP301L三種轉殖基因的小鼠;全名129-Psen1tm1Mpm Tg(APPswe, tauP301L)1Lfa/Mmjax,以下簡稱3xTg)身上,進行”二腎一夾法” (2-kidney-1-clip,以下簡稱2K1C)手術來誘導高血壓。手術1及3個月後,分別測量血壓、評估與海馬回相關的學習及記憶能力、以及檢測阿茲海默症相關的病理症狀,包括乙型類澱粉蛋白( Aβ)的量與沉澱、Tau蛋白的磷酸化程度等。第二種動物模式,係在7個月大的蘭嶼迷你豬身上,進行腹主動脈窄化手術(abdominal aortic constriction,以下簡稱AAC)來誘導高血壓。手術1、2及3個月後,進行血壓測量和阿茲海默症相關的病理症狀檢測。
結果:小鼠動物模式:2K1C手術後第7天,3個年紀3xTg小鼠的血壓即明顯上升,且至少維持一個月以上。2K1C手術後1個月,3個年紀3xTg小鼠的海馬回相關空間與非空間學習及記憶能力下降、海馬回中的Aβ濃度增加、腹側海馬回中的Aβ前驅蛋白表現量增加、以及腹側海馬回中的Tau磷酸化(pS412-Tau)程度增加,而會使Tau磷酸化的肝醣合成酶激酶-3β (GSK3β)活化程度則不受2K1C影響。此外,7個月大的3xTg小鼠,在2K1C手術3個月後,Aβ沉澱量(類澱粉斑塊)會增加。豬動物模式:AAC手術後3個月,蘭嶼迷你豬血壓明顯地上升。AAC手術後3個月,迷你豬腹側海馬回中的Aβ濃度、Aβ前驅蛋白表現量、Tau磷酸化(pT212-Tau及pS412-Tau)程度、GSK3β的活化程度、以及RAGE(Receptor of advanced glycation end product,協助Aβ穿過血腦障壁進入大腦的蛋白質)表現量增加,但是LRP-1(Low density lipoprotein receptor-related protein 1,協助Aβ穿過血腦障壁離開大腦的蛋白)的表現量與GSK3β上游激酶protein kinase B/AKT的活性則不改變。另一GSK3β上游抑制蛋白激酶C (protein kinase C)的活性,則會因AAC減少。組織免疫染色顯示AAC手術後三個月,海馬回中苔狀神經纖維Tau蛋白(pS412-Tau)的磷酸化程度增加。
結論:高血壓會增加阿茲海默症相關的病理症狀,包括學習記憶能力受損、Aβ的增加與沉澱、以及Tau蛋白的磷酸化增加。建議中年應控制血壓,或可延緩阿茲海默氏症的發病。
英文摘要 Background: Previous studies indicate an association between hypertension (HTN) and neurodegenerative disease and cognitive decline. Epidemiological studies support that middle-life HTN increases the risk of late-life Alzheimer’s disease (AD). However, whether HTN causes AD or is a distinct disease that increases the prevalence with age (co-morbidity) remains unclear.
Objective: This study aims to test if there is a causal relationship between HTN and AD.
Methods: Two animal models were used to test the role of HTN in AD pathogenesis. First, AD model mice [129-Psen1tm1Mpm Tg(APPswe,tauP301L)1Lfa/Mmjax], which express three AD related mutant genes, Psen1 M146V, APPswe and TauP301L (hereafter 3xTg), at the ages of 2, 5 and 7 months were subjected to “two-kidney-one-clip” (2K1C) surgery to induce HTN. One and three months after the surgery, the blood pressures, hippocampus-dependent learning and memory, and AD-related pathologies, including Aβ production and deposition and Tau phosphorylation, were evaluated. Second, Lanyu-miniature-pigs, at the age of 7 months, were subjected to abdominal aortic constriction (AAC) to induce HTN. The blood pressures and AD-related pathologies were determined 1, 2 and 3 months after the surgery.
Results: The 3xTg mouse study: The blood pressures of three ages 3xTg mice were increased 7 days after the 2K1C surgery and last at least 1 month later. One month after the surgery, the hippocampus-dependent non-spatial and spatial memories were impaired. Furthermore, the levels of Aβ, amyloid precursor protein, Tau phosphorylation (pS412-Tau) in the (ventral part) of hippocampi were elevated, while the levels of Tau protein kinase, GSK3β, was not affect by 2K1C surgery. In addition, 7-month-old 3xTg mice subjected to 2K1C for three months showed higher amyloid plaque loads in the hippocampi than the Sham controls. The pig study: Three months after the AAC surgery, the blood pressures of pigs were increased. Furthermore, the levels of Aβ, amyloid precursor protein, Tau phosphorylation (pT212-Tau and pS412-Tau), GSK3β activation and receptor of advanced glycation end product (facilitation of Aβ influx from blood to brain) were increased, while the levels of low-density lipoprotein receptor-related protein 1 (facilitation of Aβ efflux from brain to blood) and AKT (an upstream kinase of GSK3β) were unchanged in the ventral part of hippocampi 3 months after the AAC surgery. However, the activities of another GSK3β upstream inhibition kinase, PKC, were decreased by AAC surgery. Immunohistochemistry revealed that the expression levels of Tau phosphorylation (pS412-Tau) in the mossy fiber of hippocampi were increased three months after the AAC surgery.
Conclusion: HTN aggravates the AD-related pathologies, including impairment of hippocampus-dependent learning and memory, accumulation and deposition of Aβ and increases of Tau phosphorylation. Control of blood pressure during middle-life may delay the onset of AD.
論文目次 中文摘要..........I
Abstract...........III
致謝 ..........V
Contents..........VII
Figure Contents..........IX

I. Introduction..........1
1. Alzheimer’s disease (AD) ........1
1-1.Tau protein.........1
1-2. β-Amyloid (Aβ) peptide......3
2. 2. AD and Hypertension (HTN).......4
II. Hypothesis and Specific Aims........7
III. Materials and Methods.........8
1. Animals...........8
2. Hypertension-mouse model.........9
3. Hypertension-pig model.......10
4. Object recognition test (ORT)........12
5. Radial arm water maze........13
6. Tissue perparations........13
7. Aβ quantification.........14
8. Thioflavin-S staining.........14
9. Immunoblotting.........14
10. Immunohistochemistry........15
11. Phosphorylated Tau signal quantification......16
12. Statistical analysis........17
IV. Results...........18
1. 2K1C Induces HTN of the 3xTg Mice in different age....18
2. 2K1C Reduces Dendritic Spine Density of Hippocampal Dentate Gyrus Neurons...........19
3. 2K1C impairs hippocampus dependent, non-spatial learning and memory in 3xTg mice..........19
4. 2K1C impairs hippocampus dependent spatial learning and memory in 3xTg mice.........21
5. 2K1C increases Aβ production in 3xTg mice and accelerates deposition.22
6. 2K1C induces Tau protein hyperphosphorylation but does not with GSK3β signal pathway in 3xTg mice......23
7. AAC induce HTN in pigs........25
8. AAC increases Aβ production in pigs and increasing receptor of advanced glycation end product expression level in ventral part of hippocampus..26
9. AAC induces Tau protein hyperphosphorylation with PKC-GSK3β signal pathway in pigs.........26
V. Discussion..........29
VI. Conclusion...........33
VII. Reference...........34
VIII. Publications.........72
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