S14G-Humanin防治阿尔茨海默病的效应作用与机制研究
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摘要
研究背景与目的:阿尔茨海默病(Alzheimer’s disease,AD)是老年期痴呆最常见的原因,以进行性智能衰退为主要临床特征。神经细胞外老年斑沉积、神经元内神经原纤维缠结和神经细胞缺失是其三大病理学特征。由于缺乏特异性的临床防治措施,目前AD已成为严重危害老年人身心健康和生活质量的重要疾病之一。尽管AD的病理机制尚未完全阐明,但众多的证据表明β-淀粉样蛋白(amyloid-beta protein,Aβ)在脑内聚集、纤维化、沉积形成老年斑及其神经毒性作用是AD形成的病理学基础。因此,有效地防止或减少Aβ在脑内聚集、纤维化、沉积形成老年斑及其神经毒性作用是防治AD的重要靶点和治疗策略。Humanin(HN)及其衍生物-S14G-Humanin(HNG)是近年来发现的一种新的神经保护因子,大量体外研究表明HN和HNG能够有效地抑制目前所知的AD相关致病因子的毒性作用,但其有效作用的机制尚未阐明。本项课题将通过体外、体内实验研究,进一步深入探讨HNG防治AD的有效作用与机制。方法与结果:(1)通过体外孵育Aβ1-42、Aβ1-42+不同浓度的HNG以及细胞培养,采用荧光测定、透射电镜、细胞活性测定等方法,观察HNG拮抗Aβ1-42神经毒性的效应作用及其机制。研究结果发现,Aβ1-42组孵育3 d后,硫磺素-T(Th-T)荧光强度显著增加,透射电镜观察显示Aβ明显聚集、形成了大量的淀粉样纤维;应用不同浓度的HNG共孵育后,Th-T荧光强度随HNG浓度增加而降低,且呈剂量依赖关系,表明HNG能够有效地抑制Aβ1-42聚集及其纤维性结构的形成,投射电镜的观察结果亦进一步证明了上述研究结果。应用培养的PC12细胞研究表明HNG能够有效地抑制Aβ1-42的神经毒性作用,HNG可能通过有效减少Aβ1-42聚集和纤维性蛋白形成而发挥其神经保护作用。(2)应用侧脑室注射聚集的Aβ25-35建立小鼠AD模型,采用行为学、神经形态学、生化分析等方法,评定腹腔注射HNG对小鼠认知障碍的效应作用及其机制。Y-迷宫和跳台型被动回避行为学评定结果表明,侧脑室注射聚集的Aβ25-35可使小鼠出现显著的短期和长期学习记忆障碍,而HNG治疗可显著改善Aβ25-35导致的认知障碍;应用神经形态学和ELISA方法,研究发现在大脑皮层和海马结构Aβ25-35可导致大量的反应性星型胶质细胞、激活小胶质细胞和凋亡细胞增加,以及脑内IL-6和TNFα显著升高;而HNG治疗能够显著减少脑内的神经炎症反应和凋亡细胞,且与改善行为学障碍相平行。(3)应用幼年转APP/PS-1基因小鼠(3月龄),采用行为学评定、神经形态学等方法,进一步深入研究腹腔注射HNG防治AD病程进展的有效作用及机制。应用Morris水迷宫、被动回避和主动回避实验的行为学评定结果表明,APP/PS-1+HNG治疗组较APP/PS-1+生理盐水治疗组的行为学障碍显著减缓,提示HNG可明显改善与海马、杏仁核和皮层相关的空间学习记忆功能、伤害性刺激记忆功能和条件反射性学习记忆功能。神经形态学研究证明HNG并不影响APP/PS-1小鼠大脑皮层和海马组织弥漫性Aβ斑块的形成和数量,但可显著减少纤维性Aβ形成和斑块数量,提示在AD病理进展过程中HNG可有效地抑制纤维性Aβ形成,并可能因此降低了其神经毒性作用,进而减少病理性损害的发生,减缓了AD病程的进展。结论:(1)体外研究首次证明了HNG能够抑制Aβ1-42聚集及其纤维性结构的形成及其神经毒性作用,推测HNG可能通过减少Aβ1-42聚集和纤维性蛋白形成而发挥其神经保护作用;(2)首次研究证明了HNG对Aβ导致神经炎性反应和细胞凋亡的有效作用,同时亦证明了HNG能够通过血脑屏障进入脑内发挥其抗Aβ致认知障碍的神经保护作用;(3)首次应用转基因AD小鼠,研究HNG防治AD行为学障碍的效应作用,并应用多个行为学试验证实了HNG防治AD行为学障碍进展的有效性,其可能的机制为HNG通过抑制纤维性Aβ形成而减缓了AD的病程进展。
Background and Objective: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, characterized by progressive cognitive dysfunction. Extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and neuron loss are considered as the major neuropathological hallmarks of the disease. Since no specific and causal therapy for this disease has been developed currently, AD is unfortunately still incurable disease, which severely affects the physical and mental health as well as life quality of the elderly population. Although the pathogenesis of AD still remains unclear, increasing evidence has shown that aggregation, fibrillization, and deposition of amyloid-beta protein (Aβ) as well as formation of senile plaques and its neurotoxicity play a crucial role in the development of AD. Therefore, the important treatment targets and strategies for AD are how to effectively prevent or reduce these factors respectively. Humanin (HN) and its derivative, S14G-Humanin (HNG), is a novel 24 amino acid peptide best known for its ability to markedly suppress neuronal cell death caused by AD-related toxitic insults in vitro, however the exact mechanism that how HNG can improve the cognitive dysfunction still remains to be elucidated. By using in vitro and in vivo experiments, the aim of this study is to investigate the effect and its mechanism of HNG for preventing and treating AD. Methods and Results: (1) By using thioflavine-T fluorometric assay and transmission electron microscopy, we observed whether HNG could block/reduce the Aβ1-42 aggregation and fibrillization in vitro. The effects of HNG on the neurotoxicity of Aβ1-42 were further examined in cultured PC12 cells by MTT method. The data from thioflavine-T fluorometric assay and transmission electron microscopy disclosed that HNG could markedly inhibit fibrillar Aβformation in dose-dependent manner; by using MTT method to assay the cell activity, HNG dose-dependently reduced Aβ1-42 on the cultured PC12 cells. These findings suggest that HNG could prevent Aβ-induced neurotoxicity via inhibiting Aβaggregation and fibrillization. (2) By using a mouse AD model with intracerebroventricular injection (icv) of aggregated Aβ25-35, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Aβ25-35 in vivo. The results from this study indicate that icv injection of aggregated Aβ25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFα. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these findings demonstrate for the first time that HNG may have the potential for attenuating Aβ-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo. (3) By using young transgenic AD model (APP/PS-1 mice; 3-month-old), we investigated the effects of HNG on behavioral deficits, and Aβexpression and formation of senile plaques. The data from behavioral tests (i.e. Morris water maze, step-through test, and shuttle-box test) revealed that the behavioral deficits in APP/PS-1+HNG group were significantly improved than in APP/PS-1+saline group, suggesting that intraperitoneal HNG treatment may ameliorate behavioral deficits associated with hippocampus, amygdale, and cerebrocortex. Furthermore, neuromorphological investigation disclosed that no significant influence of HNG on diffuse Aβplaques in cerebrocortex and hippocampal region was observed in APP/PS-1 mice, while HNG might significantly reduce the fibrillar Aβformation and plaques in those regions, indicating that HNG may slow the development of AD by inhibiting Aβaggregation and fibrillization as well as reducing Aβ-induced pathological impairments. Conclusions: (1) It has been shown for the first time that HNG may effectively inhibit Aβaggregation and fibrillization and its neurotoxicity, suggesting that HNG probally plays its neuroprotective role by reducing Aβaggregation and fibrillization. (2) The study is the first to show beneficial effects of HNG on neuroinflammatory responses and apoptosis in an animal model of AD. As a result of its ability to cross the blood-brain barrier into the brain, HNG may have therapeutic potential as a protective agent against Aβ-induced cognitive dysfunction. (3) It is the first time to demonstrate beneficial effects of HNG on preventing behavioral deficits in transgenic AD models (APP/PS-1 mice), and its underlying mechanism for slowing the development of AD may be through its ability of inhibiting fibrillar Aβformation.
Background and Objective: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, characterized by progressive cognitive dysfunction. Extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and neuron loss are considered as the major neuropathological hallmarks of the disease. Since no specific and causal therapy for this disease has been developed currently, AD is unfortunately still incurable disease, which severely affects the physical and mental health as well as life quality of the elderly population. Although the pathogenesis of AD still remains unclear, increasing evidence has shown that aggregation, fibrillization, and deposition of amyloid-beta protein (Aβ) as well as formation of senile plaques and its neurotoxicity play a crucial role in the development of AD. Therefore, the important treatment targets and strategies for AD are how to effectively prevent or reduce these factors respectively. Humanin (HN) and its derivative, S14G-Humanin (HNG), is a novel 24 amino acid peptide best known for its ability to markedly suppress neuronal cell death caused by AD-related toxitic insults in vitro, however the exact mechanism that how HNG can improve the cognitive dysfunction still remains to be elucidated. By using in vitro and in vivo experiments, the aim of this study is to investigate the effect and its mechanism of HNG for preventing and treating AD. Methods and Results: (1) By using thioflavine-T fluorometric assay and transmission electron microscopy, we observed whether HNG could block/reduce the Aβ1-42 aggregation and fibrillization in vitro. The effects of HNG on the neurotoxicity of Aβ1-42 were further examined in cultured PC12 cells by MTT method. The data from thioflavine-T fluorometric assay and transmission electron microscopy disclosed that HNG could markedly inhibit fibrillar Aβformation in dose-dependent manner; by using MTT method to assay the cell activity, HNG dose-dependently reduced Aβ1-42 on the cultured PC12 cells. These findings suggest that HNG could prevent Aβ-induced neurotoxicity via inhibiting Aβaggregation and fibrillization. (2) By using a mouse AD model with intracerebroventricular injection (icv) of aggregated Aβ25-35, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Aβ25-35 in vivo. The results from this study indicate that icv injection of aggregated Aβ25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFα. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these findings demonstrate for the first time that HNG may have the potential for attenuating Aβ-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo. (3) By using young transgenic AD model (APP/PS-1 mice; 3-month-old), we investigated the effects of HNG on behavioral deficits, and Aβexpression and formation of senile plaques. The data from behavioral tests (i.e. Morris water maze, step-through test, and shuttle-box test) revealed that the behavioral deficits in APP/PS-1+HNG group were significantly improved than in APP/PS-1+saline group, suggesting that intraperitoneal HNG treatment may ameliorate behavioral deficits associated with hippocampus, amygdale, and cerebrocortex. Furthermore, neuromorphological investigation disclosed that no significant influence of HNG on diffuse Aβplaques in cerebrocortex and hippocampal region was observed in APP/PS-1 mice, while HNG might significantly reduce the fibrillar Aβformation and plaques in those regions, indicating that HNG may slow the development of AD by inhibiting Aβaggregation and fibrillization as well as reducing Aβ-induced pathological impairments. Conclusions: (1) It has been shown for the first time that HNG may effectively inhibit Aβaggregation and fibrillization and its neurotoxicity, suggesting that HNG probally plays its neuroprotective role by reducing Aβaggregation and fibrillization. (2) The study is the first to show beneficial effects of HNG on neuroinflammatory responses and apoptosis in an animal model of AD. As a result of its ability to cross the blood-brain barrier into the brain, HNG may have therapeutic potential as a protective agent against Aβ-induced cognitive dysfunction. (3) It is the first time to demonstrate beneficial effects of HNG on preventing behavioral deficits in transgenic AD models (APP/PS-1 mice), and its underlying mechanism for slowing the development of AD may be through its ability of inhibiting fibrillar Aβformation.
引文
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