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研究生：	黃慧貞 Hei-Jen Huang
論文名稱：	環境因子與Abeta1-40加成性傷害空間學習及記憶行為 The synergistic effects of environmental factors and Abeta1-40 impaired the spatial learning and memory in mice
指導教授：	謝秀梅 Hsieh, Hsiu-Mei
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：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	97
中文關鍵詞：	阿茲海默氏症、壓力、老化、高血糖、抗氧化治療、Aβ1-40蛋白質
英文關鍵詞：	Alzheimer’s disease, stress, aging, hyperglycemia, antioxidant therapy, Aβ1-40
論文種類：	學術論文
相關次數：	點閱：193 下載：5
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阿茲海默氏症(Alzheimer's Disease)於中樞神經系統內主要病變特徵之一為澱粉樣斑塊堆積。Aβ蛋白質（長約39到43個胺基酸）是穿膜本體蛋白質β-amyloid precursor protein (APP)的代謝物，是造成澱粉樣斑塊最主要之原因；大部分Aβ蛋白質為Aβ1-40與Aβ1-42。雖然Aβ1-42於澱粉樣斑塊及認知功能受損中扮演著舉足輕重的角色，但是在阿茲海默氏症早期階段時Aβ1-40的分泌量遠超過Aβ1-42；甚至有研究發現Aβ1-40在阿茲海默氏症晚期階段病因形成有所相關。因此本論文主要探討環境因子是否會提升Aβ1-40的毒性及如何造成神經退化之機轉。首先，第一個實驗所運用的環境因子為第I型糖尿病所造成的高血糖與Aβ1-40交互作用所產生的影響。結果發現，單獨高血糖或Aβ1-40都無法造成海馬回顯著性地神經退化及空間學習及記憶之損壞；但是高血糖同時併入Aβ1-40會造成Aβ1-40大量堆積、氧化壓力增加及細胞凋亡，最後導致空間學習及記憶之受損。第二個實驗主要探討老化(aged)與Aβ1-40之間的關係，所使用的老鼠為阿茲海默氏症雙基因 (APP/PS1) 突變的背景鼠種(C57BL/6J × C3H)。雖然不論何種阿茲海默氏症基因轉殖鼠均無法完全模擬人類罹患阿茲海默氏症，然而不同鼠種背景之阿茲海默氏症基因轉殖鼠其致病原因及行為受損程度卻有所差異。因為我們實驗室APP/PS1雙基因突變的基因轉殖鼠其背景鼠種為(C57BL/6J × C3H)，所以此實驗對象為C57BL/6J (母) 與 C3H (公) 交配所產生的第一子代公鼠。結果發現，老化與Aβ1-40交互作用會產生短暫性體重下降及空間記憶提取之問題；所以推測體重短暫性下降或許是老年癡呆症的早期訊號。最後一個實驗探討之環境因子是目前時下許多人所面臨之狀況—壓力，觀察壓力與Aβ1-40之間的交互作用；結果發現海馬回處出現細胞凋亡及突觸功能受損而導致嚴重的空間學習及記憶之受損。綜合以上的結果，發現Aβ1-40的毒性會受到環境因子之影響而提升而且不論哪一種環境因子與Aβ1-40相互作用都是透過氧化壓力之傷害，因此建議抗氧化壓力之治療或預防措施能延緩阿茲海默氏症病程之發展。

The deposition of beta amyloid (Aβ) as soluble or insoluble aggregates in senile plaques has been well characterized in the Alzheimer’s disease (AD) brain. Aβ peptides are composed of 39-43 amino acids derived from the soluble metabolic products of amyloid beta precursor protein (APP). Most of the soluble Aβ species comprise the species Aβ1-40 and Aβ1-42. Many studies focus on the Aβ1-42, which plays an important role in plaques and behavioral deficits in the AD. However, Aβ1-40 receives more attention in recent AD studies. A higher proportion of Aβ1-40 is present in the brain under the general condition, an increase of Aβ1-40 / Aβ1-42 ratio in cerebrospinal fluid was identified at the early stage of AD, and an important role of Aβ1-40 was identified in the pathogenesis of late-onset sporadic AD. Therefore, this dissertation worked on characterization of the effects of the interaction between environmental factors and Aβ1-40. First, we found that the neurotoxicity of Aβ1-40 could be enhanced by hyperglycemia, that enhanced the AD symptoms through the oxidative stress caused by Aβ accumulation. Second, the interaction between Aβ1-40 infusion and aged not only caused transient body-weight loss but also impaired the retrieval of spatial reference memory in the C57BL/6J × C3H hybrid mice which have been used as the common AD transgenic model, the APP/PS1 double mutant mice. Therefore, transient body-weight loss may be an important sign of early dementia with aging. Finally, the combined treatment of the stress and oligomer Aβ1-40 induced severe impairment of spatial learning and memory through apoptosis and synaptic dysfunction in the hippocampus. The above results, we suggested that the interaction between Aβ1-40 and environmental factors induced the cognitive dysfunction through the oxidative stress. Therefore, the antioxidant therapy may be a potential strategy to delay the onset of these devastating pathologies.

CHAPTER 1 Introduction    1
1.1 Characterization and classification of Alzheimer’s disease    1
1.2 Modification of amyloid cascade hypothesis    2
1.3 Nontransgenic as exogenous amyloid model versus the transgenic model of ADs    3
1.4 Aβ1-40 versus Aβ1-42    5

CHAPTER 2 Intrahippocampal administration of Aβ1–40 impairs spatial learning and memory in hyperglycemic mice    9
Abstract    9
2.1 Introduction    10
2.2 Material and methods    12
2.2.1 Animals    12
2.2.2 Experimental timeline    12
2.2.3 Hyperglycemia procedure    13
2.2.4 Preparation of oligomer and monomer Aβ1–40    13
2.2.5 Animal surgery    14
2.2.6 Morris water maze (MWM)    14
2.2.7 Histology and immunohistochemistry    16
2.2.8 Statistical analysis    17
2.3 Results and discussion    18
2.3.1 Hyperglycemia was induced by the STZ    18
2.3.2 Impaired spatial reference learning and memory of oligomer Aβ1–40-treated hyperglycemic mice    18
2.3.3 Increasing Aβ accumulation, apoptotic signal, and oxidative stress in the CA1 regions of hyperglycemic mice injected with oligomer Aβ1–40    21

CHAPTER 3 Continuous Aβ1-40 infusion affects the retrieval of spatial reference memory and body weight in C57BL/6J × C3H hybrid aging mice     34
Abstract    34
3.1 Introduction    34
3.1.1 The role of the Aβ1-40 in AD    34
3.1.2 Aging in C57BL/6J × C3H hybrid mice    35
3.2 Methods    36
3.2.1 Subjects    36
3.2.2 Procedures    36
3.2.3 Morris water maze (MWM)    37
3.2.4 Immunohistochemistry    37
3.2.5 Statistical analysis    38
3.3 Results    38
3.3.1 Transient body weight loss accompanied with apoptosis of the LH region in aging treated Aβ1-40 mice    38
3.3.2 Impairment of spatial memory    39
3.4 Discussion    40
3.5 Conclusion    43

CHAPTER 4 The interaction between acute oligomer Aβ1-40 and stress severely impaired the spatial learning and memory     51
Abstract    51
4.1 Introduction    52
4.1.1 The role of stress in AD    52
4.1.2 Hippocampus    53
4.2 Materials and methods    54
4.2.1 Subjects    54
4.2.2 Experiment timeline and establishment of the stress model    55
4.2.3 Analysis of corticosterone level    56
4.2.4 Preparation of oligomer    56
4.2.5 Animal surgery    56
4.2.6 Locomotor    57
4.2.7 Light-dark transition test    57
4.2.8 Morris water maze (MWM)    58
4.2.9 Immunohistochemistry    58
4.2.10 Western blot analysis    59
4.2.11 Data analysis    60
4.3 Results    60
4.3.1 Stress enhanced the plasma corticosterone level of treated animals    60
4.3.2 The avoidance into the dark compartment was increased with aversive experience in stress mice    61
4.3.3 Motor activity was not affected in stress mice regardless of oligomer  Aβ1-40 or vehicle treatment    61
4.3.4 Alteration of cholinergic, noradrenergic, and serotonergic immunoreactive neurons in stress and oligomer Aβ1-40 treated animals    62
4.3.5 Increasing Aβ accumulation, oxidative stress, and apoptotic signal in the stress and oligomer Aβ1–40 treated mice    63
4.3.6 Reduction of calbindin immunoreactive neurons in stress and oligomer Aβ1-40 treated mice    64
4.3.7 Increases in the GR/MR ratio and CRF-1 expression, and decreases in NF-κB and NR 2A/2B expression were observed in the hippocampus of the combined stress and oligomer Aβ1-40-treated mice    64
4.3.8 Spatial reference learning and memory was severely impaired in stress and oligomer Aβ1-40 treated mice    64
4.4 Discussion    66

CHAPTER 5 Conclusions and future prospect     81
5.1 The impacts of environmental factors on Aβ1-40    81
5.2 The potential of antioxidant therapy in AD    81
5.3 The future prospect in AD    81

References     83
Autobiographical statement     96


LIST OF TABLES
Table 1 Body weight measurements, Aβ deposition, oxidative stress, and apoptosis of the different treatment group    44
Table 2 The quantification of the immunohistochemical analyses in the different treatment mice    71

LIST OF FIGURES
Figure 1 Senile plaque and neurofibrillary tangle    7
Figure 2 Amyloid cascade hypothesis    8
Figure 3 Hyperglycemia of C57BL/6J male mice induced by STZ treatment    26
Figure 4 Effect of Aβ1–40 peptide on performance of water maze task    27
Figure 5 The Aβ1–40 injection sites confirmed by cresyl violet staining    30
Figure 6 Immunohistochemistry of Aβ1–40 deposition in the CA1 region of hippocampus    31
Figure 7 Results of caspase-3 signal showing apoptosis in the subregions of the mouse hippocampus    32
Figure 8 Results of MnSOD staining showing oxidative stress occurred in mouse brains    33
Figure 9 Effects of Aβ1–40 on mouse performance during a water maze task    45
Figure 10 Reduction of cholinergic, noradrenergic, and calbindin immunoreactive neurons in treated mice    49
Figure 11 The experimental timeline of this study    72
Figure 12 Plasma corticosterone levels in stress and nonstress mice    73
Figure 13 Anxiety evaluation of stress and nonstress mice after acute CA1 administration with oligomer Aβ1–40 and vehicle    74
Figure 14 The interactive effects of oligomer Aβ1–40 and stress on the motor activity of mice    75
Figure 15 Reduction of cholinergic, noradrenergic, and serotonergic immunoreacitve neurons in treated mice    76
Figure 16 Immunohistochemistry of Aβ1–40 accumulation, oxidative stress and apoptosis in treated mice    77
Figure 17 Calbindin expression in the CA1 subregion of hippocampus in treated mice    78
Figure 18 GR/MR ratio, CRF-1, NF-κB and NR2A/2B expressions in hippocampus of the treated mice    79
Figure 19 Interactive effects of oligmer Aβ1–40 peptide and stress on mouse performance during a water maze task    80

Figure 20 The diagram showing the interaction between Aβ1-40 and environmental factors and resulting cognitive dysfunction by oxidative stress     82

SUPPLEMENTAL DATA
(A)Experimental timeline of examining the role of the Aβ1–40 in different age hybrid mice    50
(B)The structure of Aβ1–40 after incubation at 37℃ for 7 days and 14 days    50
                                

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