臺灣博碩士論文加值系統

瞬態電壓感受器錨蛋白亞型1陽離子通道為一種非選擇性的鈣離子通道蛋白，其參與在痛覺傳導、感覺神經細胞分化、神經膠細胞發育，以及為一名控制發炎反應的看守者。然而，瞬態電壓感受器錨蛋白亞型1陽離子通道在腦部的正常生理功能以及在阿茲海默氏症的病程發展中其潛在的角色並不清楚。在本研究中，我們發現瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白功能缺失鼠出現抗焦慮行為、增加典型恐懼記憶制約反應以及增加社交偏好性；此外，瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白功能缺失鼠在空間物品認知反應以及空間記憶與學習能力上表現出更好的學習認知能力。接著我們更進一步在體內以及體外的實驗中發現在抑制或是剃除瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白的情況下，會增加神經細胞的神經軸索生長。此外，瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白功能缺失鼠改變了腦部寡突細胞的發育、降低軸突的神經束形成並降低髓鞘形成的程度，因而使得與髓鞘功能相關聯的動作行為受損。緊接著，為了釐清瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白在阿茲海默氏症病程發展中所扮演的角色，我們首先檢測瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白在阿茲海默氏症的模式動物腦部中的蛋白表達。我們發現瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白的蛋白表現的確在澱粉樣前驅蛋白/早老蛋白基因轉殖鼠的腦部與野生型小鼠相比有增加的趨勢；並且其增加的現象主要是集中在海馬迴中的星狀膠細胞中。在缺失瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白功能的澱粉樣前驅蛋白/早老蛋白基因轉殖鼠減緩了阿茲海默氏症相關的行為失能、澱粉樣蛋白的沉積以及促發炎細胞激素的製造，但卻增加了在腦部受損區域的星狀膠細胞增生。我們發現星狀膠細胞以及瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白轉殖的人類胚胎腎臟293細胞在受到纖維聚合化的澱粉樣蛋白刺激時會活化瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白並引起鈣離子的流入細胞內；而該現象則可以藉由破壞瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白的功能、藥物抑制瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白的活性或是去除細胞外的鈣離子等方式來終止。此外，抑制瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白活性則可降低在星狀膠細胞以及澱粉樣前驅蛋白/早老蛋白基因轉殖鼠腦部中受到纖維聚合化的澱粉樣蛋白的刺激所增加的蛋白去磷酸酶2B的活性。藥物抑制蛋白去磷酸酶2B的活性則能夠降低星狀膠細胞以及澱粉樣前驅蛋白/早老蛋白基因轉殖鼠腦部中受到纖維聚合化的澱粉樣蛋白刺激下所造成的發炎細胞激素製造、核因子活化B細胞輕鏈增強子與核因子活化T細胞等轉錄因子的活化以及星狀膠細胞增生。此外，抑制瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白的活性則會惡化在星狀膠細胞以及澱粉樣前驅蛋白/早老蛋白基因轉殖鼠腦部中受到澱粉樣蛋白刺激所造成的星狀膠細胞增生，但卻能夠抑制澱粉樣蛋白促進的蛋白去磷酸酶2B活化、發炎細胞激素製造、以及核因子活化B細胞輕鏈增強子與核因子活化T細胞等轉錄因子的活化。總結來說，我們的研究結果顯示瞬態電壓感受器錨蛋白亞型1陽離子通道蛋白不僅在一般情況下，對於腦部的生理功能包括神經細胞的發育以及白質的成熟過程中扮演了重要的角色，也參與在阿茲海默氏症的病程發展，更證實是透過調節星狀膠細胞造成的發炎反應，該結果提供了對於阿茲海默氏症新的治療方向以及標的。

Transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel which contributed in pain transduction, sensory neuron differentiation, development of glia cells and as a gatekeeper of inflammation. However, the potential roles of TRPA1 channel in physiological functions of brain and in the pathogenesis of Alzheimer’s disease (AD) are not fully resolved. Our data demonstrated that genetic deletion of TRPA1 channel in mice (TRPA1-/-) mediated anxiolytic behavior, increased classic fear conditioning and social preference. Moreover, TRPA1-/- mice increased ability of spatial object cognition, learning and memory. We further identified that inhibition or genetic deletion of TRPA1 activity increased the neurites outgrowth in vivo and in vitro experiments. In addition, deficient of TRPA1 channel in mice modified the development of oligodendrocytes in brain and decreased axonal bundles formation and level of myelination, thus impaired the myelin-dependent motor functions. Next, to further investigated the pathological role of TRPA1 channel in AD, we firstly examined the protein expression of TRPA1 channel in brain animal of AD. The TRPA1 expression was higher in brains, mainly astrocytes of the hippocampus, from amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) mice than wild-type mice. Ablation of TRPA1 channel function in APP/PS1 Tg mice alleviated AD-related behavioral dysfunction, amyloid  (A plaque deposition and pro-inflammatory cytokine production but increased astrogliosis in brain lesions. TRPA1 channel was activated, thus trigger Ca2+ influx in both astrocytes and TRPA1-transfected human embryonic kidney 293 cells treated with fibrilized A; these were abrogated by disruption of TRPA1 channel function, pharmacological inhibition of TRPA1 channel activity or removal of extracellular Ca2+. In addition, inhibition of TRPA1 channel activity diminished fibrilized A-increased activity of protein phosphatase 2B (PP2B, also called calcineurin) in astrocytes and in APP/PS1 Tg mice. Pharmacological inhibition of PP2B activity diminished the fibrilized Aβ–induced production of inflammatory cytokines, activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T-cells (NFAT) and astrogliosis in astrocytes. In addition, inhibition of TRPA1 channel activity exacerbated Aβ–induced astrogliosis but inhibited Aβ–mediated PP2B activation, the production of inflammatory cytokines and activities of transcriptional factors NF-κB and NFAT in astrocytes and in APP/PS1 Tg mice. These observations support the crucial role of TRPA1 channel in regulating the functions of brain which was consistent with neuron development and maturation of white matter. In AD, our findings suggest that TRPA1 channel may be a crucial regulator in astrocyte-derived inflammation and pathogenesis of AD and may be a therapeutic target for treatment of AD.

Table of Contents
Table of Contents i
致謝 xiii
Abbreviations xv
摘要 xix
Abstract xxii
Chapter 1 Introduction 1
1.1 Transient receptor potential ankyrin 1 channel 2
1.1.1 Structure and ligands of TRPA1 channel 2
1.1.2 Biological functions of TRPA1 channel 4
(1) In sensory neuron 4
(2) In brain 5
(3) In non-neuronal cell and tissue 5
1.1.3 Regulation of TRPA1 channel 6
(1) Covalent modification 6
(2) G protein-coupled receptors 7
(3) Ca2+ content 8
(4) Desensitization 9
(5) Others 10
1.2 Physiology functions of brain 10
1.2.1 Composition of brain 11
1.2.2 Neuron differentiation and behaviors outcome 11
1.2.3 Ca2+ signals in neurons differentiation 12
1.2.4 Myelination and motor function 13
1.2.5 Ca2+ signal in oligodendrocytes maturation 14
1.3 Alzheimer’s disease 15
1.3.1 Pathogenesis of AD 15
(1) Extracellular senile plaques 16
(2) Intracellular neurofibrillary tangles 17
1.3.2 Cholesterol metabolism and AD pathogenesis 17
(1) Cholesterol metabolism in brain 18
(2) Cholesterol metabolism and A production 19
(3) Cholesterol metabolism and A clearance 20
1.3.3 Ca2+ current and AD 20
1.3.4 Neuroinflammation in AD 22
1.3.5 Astrocyte in neuroinflammation of AD 22
(1) Astrogliosis 23
(2) Protein phosphatase 2B 24
(3) NF-B, NFAT and cytokines 25
1.3.6 TRP channel in AD 26
1.4 Objective 28
Chapter 2 Materials and methods 29
2.1 Reagents 30
2.2 Cell culture 31
2.3 Animals 32
2.4 Genotyping of APP/PS1 Tg/TRPA1-/- mice 33
2.5 Western blot analysis 34
2.6 Plasmid constructs 35
2.7 Transient transfection 35
2.8 siRNA transfection 36
2.9 Histology and staining 36
2.10 Immunohistochemistry staining 36
2.11 Detection of Ca2+ influx 37
2.12 Measurement of inflammatory cytokines 37
2.13 Measurement of DNA-binding activity on NF-B and NFAT 37
2.14 Measurement of PP2B activity 37
2.15 Fibrilization of A1–42 37
2.16 Open field activity test 38
2.17 Elevated plus maze 38
2.18 Classical fear conditioning 39
2.19 Social preference test 39
2.20 Hippocampus-dependent object cognition 40
2.21 Morris water maze 41
2.22 Rotarod test 42
2.23 Nest building test 42
2.24 Y-maze test 42
2.25 Statistical analysis 43
Chapter 3 Results 44
3.1 Genetic ablation of TRPA1 channel decreases anxiety-like behaviors in mice 45
3.2 Loss function of TRPA1 channel promotes both hippocampus-dependent fear-related learning and amygdala-dependent fear-related memory 45
3.3 Functional loss of TRPA1 channel in mice leads to enhanced social recognition behavior 46
3.4 TRPA1-/- mice exhibit better hippocampus-dependent learning and memory and cognition 46
3.5 Functional ablation of TRPA1 channel increases neurite integrity both in vivo and in vitro 47
3.6 Functional loss of TRPA1 channel impairs the motor function and disrupts axonal bundle organization and oligodendrocyte composition 48
3.7 The expression of TRPA1 channel is upregulated in astrocytes of AD lesions 49
3.8 Genetic loss of function of TRPA1 channel on an APP/PS1 Tg background improves nest building and spatial learning and memory 49
3.9 Deletion of TRPA1 channel function on APP/PS1 Tg background decreases Adeposition in brain lesions and mitigates inflammation but aggravates astrogliosis 51
3.10 A-elicited increase in intracellular Ca2+ in astrocytes is TRPA1-dependent 52
3.11 TRPA1 channel plays a crucial role in A-mediated inflammatory responses and astrogliosis of astrocytes 53
3.12 TRPA1-Ca2+ signaling plays a crucial role in A-mediated PP2B activation of astrocytes 54
Chapter 4 Discussion and conclusion 56
Chapter 5 Figures 70
Figure 1. The protein expression of TRPA1 channel in brain is increased during postnatal development. 71
Figure 2. Loss function of TRPA1 channel doesn’t interfere with ability of locomotion in male mice. 72
Figure 3. Loss function of TRPA1 channel doesn’t interfere with ability of locomotion in female mice. 73
Figure 4. Loss function of TRPA1 channel presents anxiolytic-like behavior in male mice. 74
Figure 5. Loss function of TRPA1 channel presents anxiolytic-like behavior in female mice. 75
Figure 6. Genetic deletion of TRPA1 channel function enhances the ability of hippocampus-dependent fear-related learning and amygdala-dependent fear-related memory in male mice. 76
Figure 7. Genetic deletion of TRPA1 channel function enhances the ability of hippocampus-dependent fear-related learning and amygdala-dependent fear-related memory in female mice. 77
Figure 8. Male TRPA1-/- mice exhibit enhanced social preference between stranger and familiar mice as interactive partners 78
Figure 9. Female TRPA1-/- mice exhibit enhanced social preference between stranger and familiar mice as interactive partners 79
Figure 10. Male TRPA1-/- mice show better performance in the hippocampus-dependent novel location recognition. 80
Figure 11. Female TRPA1-/- mice show better performance in the hippocampus-dependent novel location recognition. 81
Figure 12. Male TRPA1-/- mice require more time on learning but exhibit significant hippocampus-dependent spatial memory retention. 82
Figure 13. Female TRPA1-/- mice require more time on learning but exhibit significant hippocampus-dependent spatial memory retention. 83
Figure 14. Functional deletion of TRPA1 channel in mice doesn’t interfere with brain morphology. 84
Figure 15. TRPA1-/- mice show altered neurite structure of neuron in cortex and hippocampus. 85
Figure 16. TRPA1-/- mice show increased MAP-2 protein expression in brain. 86
Figure 17. The protein expression of TRPA1 is increased during RA-induced differentiation of Neuro-2a cells. 87
Figure18. Pharmacological inhibition of TRPA1 activity increased the neurites outgrowth in RA-induced differentiation of Neuro-2a cells. 88
Figure 19. Knock down with TRPA1 channel by siRNA increased the neurites outgrowth in RA-induced differentiation of Neuro-2a cells. 89
Figure 20. Pharmacological activation of TRPA1 activity decreased the neurites outgrowth in RA-induced differentiation of Neuro-2a cells. 90
Figure 21. Over expression of TRPA1 channel decreased the neurites outgrowth in RA-induced differentiation of Neuro-2a cells. 91
Figure 22. Male TRPA1-/- mice show impaired the motor function in rotarod test. 92
Figure 23. Female TRPA1-/- mice show impaired the motor function in rotarod test. 93
Figure 24. TRPA1-/- mice show altered axonal bundles in striatum. 94
Figure 25. TRPA1-/- mice show possess fragmented axonal bundles and decreased MBP expression. 95
Figure 26. TRPA1-/- mice exhibit deregulated oligodendrocyte maturation process in brain. 96
Figure 27. A proposed role of TRPA1 channel in neuron and oligodendrocyte development and behavior outcomes. 97
Figure 28. The protein expression TRPA1 channel is increased in APP/PS1 Tg mice than WT mice. 98
Figure 29. The TRPA1 channel is observed in endothelium of blood vessel and astrocytes in brain of WT mice. 99
Figure 30. The TRPA1 channel is observed in endothelium of blood vessel, neurons and astrocytes in brain of APP/PS1 Tg mice. 100
Figure 31. Generation of APP/PS1 Tg/TRPA1-/- mice. 101
Figure 32. APP/PS1 Tg/TRPA1-/- mice don’t show difference of locomotion activity. 102
Figure 33. Loss function of TRPA1 channel improves nest building in APP/PS1 Tg mice. 103
Figure 34. APP/PS1 Tg/TRPA1-/- mice exhibit improved ability of spatial learning and memory in Y-maze. 104
Figure 35. Loss function of TRPA1 channel improves spatial learning and memory in MWM in APP/PS1 Tg mice. 105
Figure 36. Ablation of TRPA1 channel function decreases A deposition in brain lesions of APP/PS1 Tg mice. 106
Figure 37. Loss of TRPA1 channel function decreases A expression but increases CTF level in brain of APP/PS1 Tg mice. 107
Figure 38. Ablation of TRPA1 channel function decreases ABCA1 and LRP-1 but not apoE expression in brain of APP/PS1 Tg mice. 108
Figure 39. Genetic disruption of TRPA1 channel function decreases inflammation in APP/PS1 Tg mice. 109
Figure 40. Loss of TRPA1 channel function decreases astrocyte-derived cytokines production in APP/PS1 Tg mice. 110
Figure 41. Genetic disruption of TRPA1 channel function increases astrogliosis in APP/PS1 Tg mice. 111
Figure 42. Different degree of Aβ fibrilization induces diverse inflammatory cytokine production in primary astrocytes. 112
Figure 43. Administration of A doesn’t altered protein level of TRPA1 channel in astrocytes. 113
Figure 44. A elicits Ca2+ influx in astrocytes. 114
Figure 45. Functional loss of TRPA1 channel abrogates A-induced Ca2+ influx in astrocytes. 115
Figure 46. Pharmacological inhibition of TRPA1 activity and chelation of Ca2+ diminish A-induced Ca2+ influx in astrocytes. 116
Figure 47. Overexpression of TRPA1 channel in HEK293 cells. 117
Figure 48. A elicits TRPA1-dependent Ca2+ influx in HEK293 cells. 118
Figure 49. Treatment with A and TRPA1 agonist mediate TRPA1-dependent Ca2+ influx in HEK293 cells. 119
Figure 50. Pharmacological inhibition of TRPA1 activity and chelation of Ca2+ diminish A-induced Ca2+ influx in HEK293 cells. 120
Figure 51. TRPA1 is crucial in regulating A-induced inflammatory response in astrocytes. 121
Figure 52. TRPA1 is crucial in regulating A-induced astrogliosis in astrocytes. 122
Figure 53. PP2B expression is observed on astrocytes. 123
Figure 54. Loss of TRPA1 function doesn’t alter the PP2B expression in brain. 124
Figure 55. Loss of TRPA1 function under APP/PS1 Tg background decrease PP2B activity in brain. 125
Figure 56. Genetic loss of TRPA1 diminishes A-induced PP2B activation in astrocytes. 126
Figure 57. Pharmacological inhibition of TRPA1 activity and chelation of Ca2+ diminish A-induced PP2B activation in astrocytes. 127
Figure 58. PP2B is crucial in regulating A-induced inflammatory response in astrocytes. 128
Figure 59. PP2B plays an important role in regulating A-induced astrogliosis in astrocytes. 129
Figure 60. TRPA1−Ca2+−PP2B signaling pathway in Aβ−triggered activation of NF-κB and NFAT and inflammation in astrocytes. 130
References 131

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