茶多酚对阿尔茨海默病模型的神经保护作用
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摘要
阿尔茨海默病(AD)是常见的具有年龄相关性的神经退行性疾病之一。其特点是在发病初期表现为轻微认知损伤,而后则会出现神经元变性,最终出现痴呆。2001年,全球已有2400万人患有阿尔茨海默病,这个数字预计将会在每20年翻一番,到2040年将会有8100万人患有该病。AD有两个主要的病理特征,即为在AD患者脑内,出现老年斑和神经纤维缠结,其中老年斑由β淀粉样蛋白组成,β淀粉样蛋白是由淀粉样前体蛋白(APP)剪切而得。而神经纤维缠结的主要成分是骨架蛋白tau蛋白的过磷酸化结构。随着研究的深入,研究者们提出了一些可能的发病机制,比如淀粉样蛋白聚集、沉积成老年斑的级联反应,tau蛋白过磷酸化形成纤维缠结,神经血管功能障碍以及其他的机制,例如细胞周期失调,炎性过程,氧化应激和线粒体功能障碍。
最近一段时间,有关茶多酚对于衰老和脑老化的潜在治疗作用的研究越来越多。绿茶多酚在绿茶中含量丰富,它占茶叶干重的30%-40%。茶多酚主要有四种单体,即为表没食子儿茶素没食子酸酯(epigallocatechin-3-gallate,EGCG),表儿茶素(epicatechin,EC),表没食子儿茶素((-)-epigallocatechin,EGC)和表儿茶素没食子酸酯((-)-epicatechin-gallate, ECG)。研究发现,EGCG在茶叶中含量最高,并且其生物活性最强。临床和流行病学方面的研究结果结果表明,饮用茶可以降低很多患病风险,例如,癌症,心血管疾病和糖尿病。有一些研究者认为绿茶提取物具有神经保护,神经修复的作用,而从细胞培养到动物模型都得证实了这一观点。茶多酚被认为具有多功能神经保护作用,例如抗氧化性,自由基清除剂以及铁离子螯合剂等。此外,茶多酚还有另外一个值得注意的功能,即其具有抗淀粉样性变的能力,不仅能够保护神经元受到AB的神经毒性,还能够调节APP的剪切途径,减少AB的生成。所以可见,茶多酚对于研究AD的治疗很有价值。
SAM系(快速老化小鼠)是一种较为理想的用以研究衰老相关的动物模型。该系小鼠包含有9个亚系的快速衰老小鼠(SAMP)和3个亚系的衰老抵抗小鼠(SAMR),SAMR系小鼠拥有更长的寿命,研究中作为SAMP系小鼠的正常衰老对照而存在。SAMP8小鼠是SAMP小鼠中的一系,SAMP8小鼠能够作为衰老模型,具有早发性学习和记忆功能障碍。此外,SAMP8还表现出很多AD发病早期的病理特征,如氧化应激的增强,AB的生成,tau蛋白磷酸化等等。因此,SAMP8小鼠对于研究早期和AD相关的神经退行性变是一种相当理想的动物模型。此外,有研究认为SAMP8小鼠的原代神经元和胶质细胞能够反应出一定衰老相关的变化,经过一段时间的培养后,其可表现出tau蛋白磷酸化水平的增强和快速凋亡的特性。本研究利用SAMP8原代海马神经元,培养13天,以此作为AD模型,以SAMR1原代海马神经元为对照,主要使用MTT,免疫组化,western blot, RT-PCR等方法,研究EGCG的神经保护作用,观察其对tau蛋白磷酸化的作用,并探讨可能机制。研究发现,适量的EGCG可以提高原代神经元的细胞活力,改善神经元的生长状态。EGCG可以通过激活PI3K/Akt信号途径,抑制GSK-3β的活性,减少神经元tau蛋白磷酸化水平。EGCG还可减少p35裂解为p25,以此抑制Cdk5的活性,减少tau蛋白磷酸化。EGCG可上调抗凋亡基因Bcl-2表达水平,抑制凋亡,保护细胞。
本研究以SAMP8鼠为动物模型,将茶多酚混入饮水中进行给药,研究茶多酚对SAMP8小鼠的神经保护作用。主要使用Morris水迷宫,免疫组化,银染,半定量RT-PCR,免疫印记等方法,对SAMP8小鼠和SAMR1小鼠进行研究比较。结果发现,8月龄时SAMP8小鼠已经出现明显的空间学习认知障碍,茶多酚处理之后,小鼠的空间学习认知能力有了明显提高。免疫组化实验和westernblot实验发现,茶多酚处理后的皮层和海马区域,Aβ1-42的表达水平明显降低。银染实验发现皮层和海马的神经纤维缠结也得到改善。而且,茶多酚可以激活PI3K/Akt信号途径,从而抑制GSK-3B的活性。茶多酚还可以通过调节p25/p35的比例,通过抑制Cdk5的激酶活性,以此降低动物脑内tau蛋白磷酸化水平。茶多酚可通过上调抗凋亡基因Bcl-2的mRNA表达水平和蛋白表达水平,抑制凋亡保护细胞。可见,长期应用茶多酚可以能通过多种途径够减少tau蛋白磷酸化水平以及Aβ1-42蛋白生成,茶多酚神经保护作用的机制可由其激活PI3K/Akt信号转导通路来实现。
本研究的结果为茶多酚的神经保护理论提供了一些新的证据,为预防和治疗AD提供了一些新的思路。
Alzheimer's disease (AD) is one of the most prevalent age-dependent neurodegenerative disorders. It is characterized by mild cognitive impairment at its onset followed by irreversible neuronal degeneration and dementia later. In2001, more than24million people had dementia. The number is expected to double every20years up to81million in2040because of the anticipated increase in life expectancy. AD is characterized by presence of two aberrant structures in the patients'brains, senile plaques and neurofibrillary tangles. Senile plaques are composed of beta amyloid peptide, a fragment of the amyloid peptide precursor, whereas the main component of neurofibrillary tangles is the cytoskeleton protein known as the tau protein, in hyperphosphorylated form. Several pathogenic mechanisms that underlie these changes have been studied, including A13aggregation and deposition with plaque development, tau hyperphosphorylation with tangle formation, neurovascular dysfunction, and other mechanisms such as cell-cycle abnormalities, inflammatory processes, oxidative stress, and mitochondrial dysfunction.
Recently, there is growing interest in the potential beneficial effects of green tea polyphenols (GTP) on aging and aged brain. Green tea catechins, are especially concentrated in green tea. It accounts for30-40%of the dry weight of the leaves. The major polyphenolic components in GTP are epigallocatechin-3-gallate (EGCG), epicatechin (EC),(-)-epigallocatechin (EGC) and (-)-epicatechin-gallate(ECG). Among these components, EGCG is the abundant and most active component.There is abundant of evidence, which is mostly from the preclinical and epidemiological studies, suggesting that green tea consumption is associated with a reduced risk of severe human malignancies such as cancer, cardiovascular diseases, and diabetes. More recently, either the green tea extract or its isolated catechin constituents have been reported to display neuroprotective/neurorestorative properties. A lot of studies have demonstrated that GTP exhibit multifunctional neuroprotective-neurorescue activities in cell cultures and animal models, such as antioxidant actions, free radical scavenging and iron-chelating properties. Another noteworthy feature of GTP is that they possess anti-amyloidogenic effects, protecting neuron from A_-induced neurotoxicity and regulating APP processing in vitro and in vivo. GTP may be a novel neuroprotective strategy for AD.
SAM(The senescence-accelerated mouse), is a well established animal model foraging. It is a group of related inbredstrains including nine strains of accelerated-prone, short-lived mice (SAMP), and three strains of accelerated senescence-resistant, long-lived mice (SAMR). Senescence-accelerated mouse prone-8(SAMP8), a substrain of SAMP, shows early onset of learning and memory deficits. What's more, senescence-accelerated mouse (SAMP8), which could act as a model of aging, displays many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD. And in addition, it was reported that hyperphosphorylation in some forms of tau, protein kinase GSK-3β and Cdk5activation, and increase in overall oxidative stress status in primary neurons and astrocytes of SAMP8. Therefore, we investigate the protective mechanisms of EGCG on SAMP8primary hippocampus neurons, which would be cultured for at least13days. MTT method, immunohistochemistry,RT-PCR, Western Blot were employed in this experiment. And it is revealed that, after incubated with EGCG, the growth appearance of primary neurons was improved. And EGCG could inhibit the activation of GSK-3βkinase via the PI3K/Akt pathway, subsequently resulting in less tau phosphorylation. Besides, EGCG could also decrease the activity of Cdk5through reducing p25/p35ratio which suppressed tau phosphorylation. EGCG could up-regulates the Bcl-2mRNA and protein expression, which would inhibit the cell apoptosis.
Taken SAMP8mice as the AD animal model, we investigated the neuroprotective effect of GTP, with such method as Morris water maze(MWM), immunohistochemical staining, RT-PCR and western blot. Results show with long-term oral administration of GTP, that the spatial learning and memory of SAMP8in MWM were improved significantly. Immunohistochemical straining shows that the Aβ1-42positive cells in both cortex and hippocampus were reduced. It is also proved that NFTs observed with Bielschowsky method decreased after GTP treatment. And, long term GTP administration reduced the Aβ1-42level in cortex and hippocampus, inhibited the GSK-3Bactivity via PI3K/Akt pathway, decreased the Cdk5activity by modulating p25/p35ratio, subsequently reduced the tau phosphorylation. Bcl-2level was up-regulated after the GTP treatment. These results suggest that long-term GTP administration down-regulated Aβ1-42protein levels and tau phosphorylation with probable multiple pathways including PI3K/Akt pathway.
The experimental results of present study support the neuroprotection of GTP and provide a new strategy of preventing and curing Alzheimer's Disease.
最近一段时间,有关茶多酚对于衰老和脑老化的潜在治疗作用的研究越来越多。绿茶多酚在绿茶中含量丰富,它占茶叶干重的30%-40%。茶多酚主要有四种单体,即为表没食子儿茶素没食子酸酯(epigallocatechin-3-gallate,EGCG),表儿茶素(epicatechin,EC),表没食子儿茶素((-)-epigallocatechin,EGC)和表儿茶素没食子酸酯((-)-epicatechin-gallate, ECG)。研究发现,EGCG在茶叶中含量最高,并且其生物活性最强。临床和流行病学方面的研究结果结果表明,饮用茶可以降低很多患病风险,例如,癌症,心血管疾病和糖尿病。有一些研究者认为绿茶提取物具有神经保护,神经修复的作用,而从细胞培养到动物模型都得证实了这一观点。茶多酚被认为具有多功能神经保护作用,例如抗氧化性,自由基清除剂以及铁离子螯合剂等。此外,茶多酚还有另外一个值得注意的功能,即其具有抗淀粉样性变的能力,不仅能够保护神经元受到AB的神经毒性,还能够调节APP的剪切途径,减少AB的生成。所以可见,茶多酚对于研究AD的治疗很有价值。
SAM系(快速老化小鼠)是一种较为理想的用以研究衰老相关的动物模型。该系小鼠包含有9个亚系的快速衰老小鼠(SAMP)和3个亚系的衰老抵抗小鼠(SAMR),SAMR系小鼠拥有更长的寿命,研究中作为SAMP系小鼠的正常衰老对照而存在。SAMP8小鼠是SAMP小鼠中的一系,SAMP8小鼠能够作为衰老模型,具有早发性学习和记忆功能障碍。此外,SAMP8还表现出很多AD发病早期的病理特征,如氧化应激的增强,AB的生成,tau蛋白磷酸化等等。因此,SAMP8小鼠对于研究早期和AD相关的神经退行性变是一种相当理想的动物模型。此外,有研究认为SAMP8小鼠的原代神经元和胶质细胞能够反应出一定衰老相关的变化,经过一段时间的培养后,其可表现出tau蛋白磷酸化水平的增强和快速凋亡的特性。本研究利用SAMP8原代海马神经元,培养13天,以此作为AD模型,以SAMR1原代海马神经元为对照,主要使用MTT,免疫组化,western blot, RT-PCR等方法,研究EGCG的神经保护作用,观察其对tau蛋白磷酸化的作用,并探讨可能机制。研究发现,适量的EGCG可以提高原代神经元的细胞活力,改善神经元的生长状态。EGCG可以通过激活PI3K/Akt信号途径,抑制GSK-3β的活性,减少神经元tau蛋白磷酸化水平。EGCG还可减少p35裂解为p25,以此抑制Cdk5的活性,减少tau蛋白磷酸化。EGCG可上调抗凋亡基因Bcl-2表达水平,抑制凋亡,保护细胞。
本研究以SAMP8鼠为动物模型,将茶多酚混入饮水中进行给药,研究茶多酚对SAMP8小鼠的神经保护作用。主要使用Morris水迷宫,免疫组化,银染,半定量RT-PCR,免疫印记等方法,对SAMP8小鼠和SAMR1小鼠进行研究比较。结果发现,8月龄时SAMP8小鼠已经出现明显的空间学习认知障碍,茶多酚处理之后,小鼠的空间学习认知能力有了明显提高。免疫组化实验和westernblot实验发现,茶多酚处理后的皮层和海马区域,Aβ1-42的表达水平明显降低。银染实验发现皮层和海马的神经纤维缠结也得到改善。而且,茶多酚可以激活PI3K/Akt信号途径,从而抑制GSK-3B的活性。茶多酚还可以通过调节p25/p35的比例,通过抑制Cdk5的激酶活性,以此降低动物脑内tau蛋白磷酸化水平。茶多酚可通过上调抗凋亡基因Bcl-2的mRNA表达水平和蛋白表达水平,抑制凋亡保护细胞。可见,长期应用茶多酚可以能通过多种途径够减少tau蛋白磷酸化水平以及Aβ1-42蛋白生成,茶多酚神经保护作用的机制可由其激活PI3K/Akt信号转导通路来实现。
本研究的结果为茶多酚的神经保护理论提供了一些新的证据,为预防和治疗AD提供了一些新的思路。
Alzheimer's disease (AD) is one of the most prevalent age-dependent neurodegenerative disorders. It is characterized by mild cognitive impairment at its onset followed by irreversible neuronal degeneration and dementia later. In2001, more than24million people had dementia. The number is expected to double every20years up to81million in2040because of the anticipated increase in life expectancy. AD is characterized by presence of two aberrant structures in the patients'brains, senile plaques and neurofibrillary tangles. Senile plaques are composed of beta amyloid peptide, a fragment of the amyloid peptide precursor, whereas the main component of neurofibrillary tangles is the cytoskeleton protein known as the tau protein, in hyperphosphorylated form. Several pathogenic mechanisms that underlie these changes have been studied, including A13aggregation and deposition with plaque development, tau hyperphosphorylation with tangle formation, neurovascular dysfunction, and other mechanisms such as cell-cycle abnormalities, inflammatory processes, oxidative stress, and mitochondrial dysfunction.
Recently, there is growing interest in the potential beneficial effects of green tea polyphenols (GTP) on aging and aged brain. Green tea catechins, are especially concentrated in green tea. It accounts for30-40%of the dry weight of the leaves. The major polyphenolic components in GTP are epigallocatechin-3-gallate (EGCG), epicatechin (EC),(-)-epigallocatechin (EGC) and (-)-epicatechin-gallate(ECG). Among these components, EGCG is the abundant and most active component.There is abundant of evidence, which is mostly from the preclinical and epidemiological studies, suggesting that green tea consumption is associated with a reduced risk of severe human malignancies such as cancer, cardiovascular diseases, and diabetes. More recently, either the green tea extract or its isolated catechin constituents have been reported to display neuroprotective/neurorestorative properties. A lot of studies have demonstrated that GTP exhibit multifunctional neuroprotective-neurorescue activities in cell cultures and animal models, such as antioxidant actions, free radical scavenging and iron-chelating properties. Another noteworthy feature of GTP is that they possess anti-amyloidogenic effects, protecting neuron from A_-induced neurotoxicity and regulating APP processing in vitro and in vivo. GTP may be a novel neuroprotective strategy for AD.
SAM(The senescence-accelerated mouse), is a well established animal model foraging. It is a group of related inbredstrains including nine strains of accelerated-prone, short-lived mice (SAMP), and three strains of accelerated senescence-resistant, long-lived mice (SAMR). Senescence-accelerated mouse prone-8(SAMP8), a substrain of SAMP, shows early onset of learning and memory deficits. What's more, senescence-accelerated mouse (SAMP8), which could act as a model of aging, displays many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD. And in addition, it was reported that hyperphosphorylation in some forms of tau, protein kinase GSK-3β and Cdk5activation, and increase in overall oxidative stress status in primary neurons and astrocytes of SAMP8. Therefore, we investigate the protective mechanisms of EGCG on SAMP8primary hippocampus neurons, which would be cultured for at least13days. MTT method, immunohistochemistry,RT-PCR, Western Blot were employed in this experiment. And it is revealed that, after incubated with EGCG, the growth appearance of primary neurons was improved. And EGCG could inhibit the activation of GSK-3βkinase via the PI3K/Akt pathway, subsequently resulting in less tau phosphorylation. Besides, EGCG could also decrease the activity of Cdk5through reducing p25/p35ratio which suppressed tau phosphorylation. EGCG could up-regulates the Bcl-2mRNA and protein expression, which would inhibit the cell apoptosis.
Taken SAMP8mice as the AD animal model, we investigated the neuroprotective effect of GTP, with such method as Morris water maze(MWM), immunohistochemical staining, RT-PCR and western blot. Results show with long-term oral administration of GTP, that the spatial learning and memory of SAMP8in MWM were improved significantly. Immunohistochemical straining shows that the Aβ1-42positive cells in both cortex and hippocampus were reduced. It is also proved that NFTs observed with Bielschowsky method decreased after GTP treatment. And, long term GTP administration reduced the Aβ1-42level in cortex and hippocampus, inhibited the GSK-3Bactivity via PI3K/Akt pathway, decreased the Cdk5activity by modulating p25/p35ratio, subsequently reduced the tau phosphorylation. Bcl-2level was up-regulated after the GTP treatment. These results suggest that long-term GTP administration down-regulated Aβ1-42protein levels and tau phosphorylation with probable multiple pathways including PI3K/Akt pathway.
The experimental results of present study support the neuroprotection of GTP and provide a new strategy of preventing and curing Alzheimer's Disease.
引文
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