阿尔茨海默症模型细胞的钙信号研究
摘要
阿尔茨海默症(Alzheimer’s Disease,AD)是一种神经退行性疾病。AD患者临床上表现为记忆、语言、感觉和运动功能的进行性损害,性格和情感控制等方面的异常。随着人类老龄化社会的到来,阿尔茨海默症已成为医学和社会面临的严峻问题。
但至今为止,AD的发病机理仍不清楚。普遍认为,Aβ(Amyloid-β)在AD的病理机制中处于中心地位。另一方面,AD神经元出现钙信号紊乱也是不容置疑的。在神经系统中,钙信号有多种调节功能,如突触的可塑性、神经元的凋亡等。Aβ和Tau蛋白诱发的神经退化很可能是由细胞钙信号紊乱介导实现的。不仅如此,研究已经证实家族性AD基因突变会对细胞的钙信号通路产生影响。作为第二信使的钙离子可能在AD的发病机理中扮演着重要的角色,因此AD的细胞钙信号研究对阐明AD的机理是有益的。
本论文以转基因AD模型细胞为材料,利用激光共聚焦扫描显微镜成像技术,系统地研究了AD模型细胞的钙信号紊乱情况。
本文的主要内容及结果如下:
一、对神经瘤细胞和海马神经元进行形态和功能研究,对神经瘤细胞作为AD钙信号研究模型细胞的可行性进行了初步验证。 从实验结果得知,在合适浓度的细胞分化诱导剂视黄酸(Retinoic Acid, RA)诱导下,N2a(Neuroblastoma Cell,Mouse)细胞向与神经元类似的形态分化,可以形成类似于神经元的轴突,甚至神经元间的网络状结构;实验中还发现有的诱导细胞形态非常接近于星型胶质细胞。
在神经科学的研究中,对生理和病理状态下Ca~(2+)波动研究是探讨许多疾病机理的重要途径之一。而细胞的K+极化刺激诱发的Ca~(2+)波动是一个经典实验。K~+极化刺激诱发的Ca~(2+)波动实验结果显示,N2a细胞和海马神经元的Ca~(2+)波动非常相似。此实验结果也进一步表明:用N2a细胞代替原代海马神经元进行AD致病机理的Ca~(2+)信号的功能性研究是可行的。
N2a细胞的可传代性、可诱导分化性和与神经元钙信号的相似性可以满足AD钙信号研究的要求。
二、APP695 基因突变对细胞钙信号的影响。
Alzheimer’s Disease(AD) is a progressive and irreversible neurodegenerative disorderthat leads to cognitive, memory and behavioural impairments. The pathogenesis ofAlzheimer’s Disease is complex, and involves many molecular, cellular and physiologicalpathologies. With the coming of aging society, the correspongding research attracts moreand more attention in the world. However, its pathogenic mechanism is still poorlyunderstood now. Calcium modulates many neural processes, including synaptic plasticityand apoptosis. It is irrefutable that calcium dysregulation is involved in theneurodegeneration of Alzheimer’s Disease. Neurodegeneration that is induced byamyloid-βor tau protein is probably mediated by changes in calcium homeostasis.Moreover, mutations that cause familial Alzheimer’s Disease have been linked tointracellular calcium signalling pathways. Destabilization of calcium signalling seems to be akey factor in the pathogenesis of Alzheimer’s Disease, and drug design targeting this processmight be therapeutically promising.
Using the image technology of confocal laser scanning microscope, we studied themechanism of the calcium dysregulation of the AD model cell s.
Three aspects of work were designed and have performed in the research:
In the first part of the dissertation, to test the feasibility of using N2a cell as model cellin AD calcium signal, we studied the morphological and functional differences between N2aand hippocampus neuron. After being treated by 10-5 uM RA(Retinioc Acid) for 7 days, N2acell could grow axon and form network .The result of K+ depolarization stimulationexperiment indicate that the Ca~(2+) wave of N2a cell was closed to hippocamp neron. Fromthese resulst, we can conform that using N2a cell as model cell in AD calcium signal isviable.
In the second part of the dissertation, we employed the image technology of confocallaser scanning microscope to study the interaction between APP695(amyloid precusorprotein 695,APP695 ) mutation and calcium dysregulation. At present, calcium dysregulation
但至今为止,AD的发病机理仍不清楚。普遍认为,Aβ(Amyloid-β)在AD的病理机制中处于中心地位。另一方面,AD神经元出现钙信号紊乱也是不容置疑的。在神经系统中,钙信号有多种调节功能,如突触的可塑性、神经元的凋亡等。Aβ和Tau蛋白诱发的神经退化很可能是由细胞钙信号紊乱介导实现的。不仅如此,研究已经证实家族性AD基因突变会对细胞的钙信号通路产生影响。作为第二信使的钙离子可能在AD的发病机理中扮演着重要的角色,因此AD的细胞钙信号研究对阐明AD的机理是有益的。
本论文以转基因AD模型细胞为材料,利用激光共聚焦扫描显微镜成像技术,系统地研究了AD模型细胞的钙信号紊乱情况。
本文的主要内容及结果如下:
一、对神经瘤细胞和海马神经元进行形态和功能研究,对神经瘤细胞作为AD钙信号研究模型细胞的可行性进行了初步验证。 从实验结果得知,在合适浓度的细胞分化诱导剂视黄酸(Retinoic Acid, RA)诱导下,N2a(Neuroblastoma Cell,Mouse)细胞向与神经元类似的形态分化,可以形成类似于神经元的轴突,甚至神经元间的网络状结构;实验中还发现有的诱导细胞形态非常接近于星型胶质细胞。
在神经科学的研究中,对生理和病理状态下Ca~(2+)波动研究是探讨许多疾病机理的重要途径之一。而细胞的K+极化刺激诱发的Ca~(2+)波动是一个经典实验。K~+极化刺激诱发的Ca~(2+)波动实验结果显示,N2a细胞和海马神经元的Ca~(2+)波动非常相似。此实验结果也进一步表明:用N2a细胞代替原代海马神经元进行AD致病机理的Ca~(2+)信号的功能性研究是可行的。
N2a细胞的可传代性、可诱导分化性和与神经元钙信号的相似性可以满足AD钙信号研究的要求。
二、APP695 基因突变对细胞钙信号的影响。
Alzheimer’s Disease(AD) is a progressive and irreversible neurodegenerative disorderthat leads to cognitive, memory and behavioural impairments. The pathogenesis ofAlzheimer’s Disease is complex, and involves many molecular, cellular and physiologicalpathologies. With the coming of aging society, the correspongding research attracts moreand more attention in the world. However, its pathogenic mechanism is still poorlyunderstood now. Calcium modulates many neural processes, including synaptic plasticityand apoptosis. It is irrefutable that calcium dysregulation is involved in theneurodegeneration of Alzheimer’s Disease. Neurodegeneration that is induced byamyloid-βor tau protein is probably mediated by changes in calcium homeostasis.Moreover, mutations that cause familial Alzheimer’s Disease have been linked tointracellular calcium signalling pathways. Destabilization of calcium signalling seems to be akey factor in the pathogenesis of Alzheimer’s Disease, and drug design targeting this processmight be therapeutically promising.
Using the image technology of confocal laser scanning microscope, we studied themechanism of the calcium dysregulation of the AD model cell s.
Three aspects of work were designed and have performed in the research:
In the first part of the dissertation, to test the feasibility of using N2a cell as model cellin AD calcium signal, we studied the morphological and functional differences between N2aand hippocampus neuron. After being treated by 10-5 uM RA(Retinioc Acid) for 7 days, N2acell could grow axon and form network .The result of K+ depolarization stimulationexperiment indicate that the Ca~(2+) wave of N2a cell was closed to hippocamp neron. Fromthese resulst, we can conform that using N2a cell as model cell in AD calcium signal isviable.
In the second part of the dissertation, we employed the image technology of confocallaser scanning microscope to study the interaction between APP695(amyloid precusorprotein 695,APP695 ) mutation and calcium dysregulation. At present, calcium dysregulation
引文
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