金思维提取物对AD模型鼠脑内β淀粉样肽及神经可塑性的影响
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摘要
目的:基于阿尔茨海默病(AD)发病机理中的“Aβ级联假说”,研究金思维提取物对AD动物模型脑内Aβ的生成、聚集和降解途径及神经元可塑性的影响,探讨金思维提取物治疗AD的作用靶点。
方法:选用APPV717I转基因小鼠AD模型和Aβ1-42海马注射所致AD大鼠模型,采用Morris水迷宫、免疫组织化学、Western blot、电镜以及图像分析技术等手段,观测模型小鼠行为学和脑内淀粉样斑块的变化及APP、Aβ、BACE、PS1、IDE和NEP的含量和表达水平;观测模型大鼠海马轴突的超微结构变化及β-actin、β-tubulin、MBP、GAP43和NGF的表达水平。
结果:金思维组大、小鼠逃避潜伏期和游泳距离较模型组明显缩短,穿越原平台所在位置次数明显增加(P<0.05/P<0.01);金思维组小鼠脑内淀粉样斑块较模型组明显减少(P<0.01),脑内APP、Aβ、BACE和PS1的含量及表达水平较模型组下调(P<0.05/P<0.01),IDE和NEP的含量及表达水平较模型组上调(P<0.05/P<0.01);金思维大鼠海马轴突结构清晰完整,β-actin、β-tubulin、MBP、GAP43和NGF的表达水平上调,与模型组比较有显著性差异(P<0.05/P<0.01)。
结论:金思维提取物对AD的干预作用机制主要是:一方面通过下调APP及其β、γ分泌酶的表达,减少Aβ的生成和聚集;上调Aβ脑内降解酶IDE和NEP的表达,增加Aβ的清除,从而减轻Aβ的神经毒性;另一方面,通过改善神经营养,促进对轴突和突触损伤的修复,提高神经可塑性,从而改善学习记忆能力。
Objective: According to beta-amyloid (Aβ) cascade hypothesis in Alzheimer’s disease(AD), this study is to observe effects of GETO (herbal extract) on generation and degradation of beta-amyloid protein and neuron plasticity, to look for effective target of GETO in the treating AD. Methods: APPV717I transgenic mouse and model rats with hippocampus injected by Aβ1-42, as AD models were used in this study. Morris water maze test was used to screen learning and memory impairmed animals. Congo red staining, immunohistochemistry(IHC), Western blot, electronmicroscope and system of image pro-plus were used to determine amyloid plaques, protein expression of APP,Aβ,BACE,PS1,IDE and NEP in the brain of APPV717I transgenic mouse, as well as ultramicro- structure of axons and protein expression ofβ-actin,β-tubulin,MBP,GAP43 and NGF in the hippocampus of model rats induced by Aβ1-42. Results: Morris water maze test showed that the escape latency and swimming distance of GETO group is significantly shorter than model group(p<0.05/0.01),but the times of crossing platform is much more than model group (p<0.05/0.01).Amyloid plaques in GETO group is significantly decreased compared to model group(p<0.05/0.01). Comparing to model group, the levels of expression of APP, Aβ, BACE and PS1 in the brain of mice in GETO group are significantly decreased (p<0.05/0.01); the levels of expression of IDE and NEP in the brain of mice in GETO group are significantly increased(p<0.05/0.01); And also the levels of expression ofβ-actin,β-tubulin, MBP,GAP43 and NGF in the hippocampus of rats in GETO group are significantly increased(p<0.05/0.01). Under electronmicroscope, there were obvious lysis of the axon microtubule, faintness of microfilamen and rarefaction of the synapsis of the neurophils of hippocampus CA1 in the model rats. In GETO group,the normal microfilament was clearly seen,the microtubule of the rats’hippocampus neuron axons was tidily arrayed; the increased synapsis of the neurophils could be seen. Conclusion: Mechanisms of GETO extract effective in the interventing AD are explained as follow. On the one hand,GETO can decreases the expression of APP and itsβ-andγ-secretase and increase the expression of IDE and NEP, to balance generation, accumulation and aggradation of Aβ, and to alleviate neuron toxicity in the AD brain.On the other hand,GETO can renovate damaged axons, improve neuroal nutrition, thereby ameliorate neuron plasticity and learning and memory peformance of AD models.
方法:选用APPV717I转基因小鼠AD模型和Aβ1-42海马注射所致AD大鼠模型,采用Morris水迷宫、免疫组织化学、Western blot、电镜以及图像分析技术等手段,观测模型小鼠行为学和脑内淀粉样斑块的变化及APP、Aβ、BACE、PS1、IDE和NEP的含量和表达水平;观测模型大鼠海马轴突的超微结构变化及β-actin、β-tubulin、MBP、GAP43和NGF的表达水平。
结果:金思维组大、小鼠逃避潜伏期和游泳距离较模型组明显缩短,穿越原平台所在位置次数明显增加(P<0.05/P<0.01);金思维组小鼠脑内淀粉样斑块较模型组明显减少(P<0.01),脑内APP、Aβ、BACE和PS1的含量及表达水平较模型组下调(P<0.05/P<0.01),IDE和NEP的含量及表达水平较模型组上调(P<0.05/P<0.01);金思维大鼠海马轴突结构清晰完整,β-actin、β-tubulin、MBP、GAP43和NGF的表达水平上调,与模型组比较有显著性差异(P<0.05/P<0.01)。
结论:金思维提取物对AD的干预作用机制主要是:一方面通过下调APP及其β、γ分泌酶的表达,减少Aβ的生成和聚集;上调Aβ脑内降解酶IDE和NEP的表达,增加Aβ的清除,从而减轻Aβ的神经毒性;另一方面,通过改善神经营养,促进对轴突和突触损伤的修复,提高神经可塑性,从而改善学习记忆能力。
Objective: According to beta-amyloid (Aβ) cascade hypothesis in Alzheimer’s disease(AD), this study is to observe effects of GETO (herbal extract) on generation and degradation of beta-amyloid protein and neuron plasticity, to look for effective target of GETO in the treating AD. Methods: APPV717I transgenic mouse and model rats with hippocampus injected by Aβ1-42, as AD models were used in this study. Morris water maze test was used to screen learning and memory impairmed animals. Congo red staining, immunohistochemistry(IHC), Western blot, electronmicroscope and system of image pro-plus were used to determine amyloid plaques, protein expression of APP,Aβ,BACE,PS1,IDE and NEP in the brain of APPV717I transgenic mouse, as well as ultramicro- structure of axons and protein expression ofβ-actin,β-tubulin,MBP,GAP43 and NGF in the hippocampus of model rats induced by Aβ1-42. Results: Morris water maze test showed that the escape latency and swimming distance of GETO group is significantly shorter than model group(p<0.05/0.01),but the times of crossing platform is much more than model group (p<0.05/0.01).Amyloid plaques in GETO group is significantly decreased compared to model group(p<0.05/0.01). Comparing to model group, the levels of expression of APP, Aβ, BACE and PS1 in the brain of mice in GETO group are significantly decreased (p<0.05/0.01); the levels of expression of IDE and NEP in the brain of mice in GETO group are significantly increased(p<0.05/0.01); And also the levels of expression ofβ-actin,β-tubulin, MBP,GAP43 and NGF in the hippocampus of rats in GETO group are significantly increased(p<0.05/0.01). Under electronmicroscope, there were obvious lysis of the axon microtubule, faintness of microfilamen and rarefaction of the synapsis of the neurophils of hippocampus CA1 in the model rats. In GETO group,the normal microfilament was clearly seen,the microtubule of the rats’hippocampus neuron axons was tidily arrayed; the increased synapsis of the neurophils could be seen. Conclusion: Mechanisms of GETO extract effective in the interventing AD are explained as follow. On the one hand,GETO can decreases the expression of APP and itsβ-andγ-secretase and increase the expression of IDE and NEP, to balance generation, accumulation and aggradation of Aβ, and to alleviate neuron toxicity in the AD brain.On the other hand,GETO can renovate damaged axons, improve neuroal nutrition, thereby ameliorate neuron plasticity and learning and memory peformance of AD models.
引文
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