基于Aβ神经毒性的脑力健代谢组学研究
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摘要
阿尔茨海默病(Alzheimer disease, AD)是一种原因未明的神经系统的退行性病变,以脑的广泛神经细胞凋亡、胞外老年斑(senile plague, SP)沉积、胞内神经原纤维缠结(neuro fibrillary tangles, NFT)以及皮层和海马神经细胞减少为主要病理改变。根据AD“肾虚毒损”的病机拟定的中药复方脑力健具有补肾健脑、解毒益智的功效。β淀粉样蛋白(amyloid β-protein, Aβ)神经毒性是AD发生发展过程中的重要因素,也是近年来中药抗AD研究的热点标靶。代谢组学是对中药复方整体效应评价的有效方法之一。本研究主要进行了脑力健对Aβ诱导的AD大鼠学习记忆能力、海马形态学、海马神经毒性的影响,以及对AD大鼠代谢组学的影响。
目的：探讨脑力健对AD大鼠A β神经毒性的改善作用及其机制,初步揭示AD大鼠的体内物质变化和代谢途径变化以及脑力健对AD大鼠代谢途径的干预作用。
方法：用聚集状态的Aβ25-35大鼠双侧海马注射建立AD模型,药物干预后,Morris水迷宫观察脑力健对AD大鼠学习记忆能力的影响,病理观察脑力健对AD大鼠脑形态学的影响,用免疫组化的方法检测大鼠海马IDE、cdk5、GSK-3、SYN的表达和平均光密度,收集代谢产物后经过样本处理、测试、数据处理等步骤观察脑力健对AD大鼠代谢组学的影响。
结果：
1.脑力健对AD大鼠学习记忆功能的影响定位航行实验显示,模型对照组大鼠的逃避潜伏期均显著延长；给药各组与模型组比较,大鼠逃避潜伏期均显著缩短,有显著统计学意义(P<0.05)。空间探索实验显示模型组在第一象限时间和平台停留时间显著缩短,经过平台次数显著减少；而给药组第一象限时间和平台停留时间均较模型对照组显著延长、经过平台次数显著增多,有显著的统计学意义(P<0.05)。
2.脑力健对A β海马注射痴呆模型脑病理形态学的影响结果显示,模型纽多数病例不同程度神经细胞减少,神经元凋亡及胶质细胞增生；给药组较模型对照组其神经细胞凋亡、CA1区水肿、胶质细胞增生等情况均显著减轻。
3.脑力健对A β海马注射痴呆模型Aβ降解酶IDE表达的影响研究表明,模型对照组IDE阳性免疫反应产物呈显著低表达,脑力健高、中剂量组较模型对照组阳性表达显著增高。模型对照组海马区IDE平均光密度值较空白对照组显著降低(P<0.01),脑力健各剂量组与模型对照组比较则显著增高(P<0.05)
4.脑力健对A β注射痴呆鼠海马区CDK5表达的影响研究表明,模型组较假手术组其cdk5有显著高表达,脑力健各组cdk5的表达均明显低于模型组。模型组海马区的cdk5平均光密度值较空白对照组显著增高(P<0.01),脑力健各给药组与模型对照组比较显著降低,有显著的统计学意义(P<0.05)。
5.脑力健对A β注射痴呆鼠海马区GSK-3表达的影响研究显示,A β海马注射后各组大鼠海马CA1区均可见GSK-3的阳性反应物,模型组GSK-3表达较假手术组明显增多,脑力健各剂量组染色结果与假手术组相似,表达显著减少；模型对照组海马区平均光密度值较空白对照组显著增高(P<0.01),提示模型组海马GSK-3活性显著增强；脑力健各组与模型对照组GSK-3的平均光密度比较则显著降低(P<0.01),但组间无显著差异(P>0.05)
6.脑力健对A β注射痴呆鼠海马区SYN表达的影响研究显示,假手术组的SYN表达高于模型组,差异具有显著性(P<0.05)；脑力健各给药组海马区突出素的表达均明显高于模型组(P<0.01)。模型对照组海马区SYN平均光密度值较假手术组显著降低(P<0.01),脑力键高、中、低剂量组与模型对照组比较,平均光密度值显著增高(P<0.05)。
7.脑力健对A β注射痴呆鼠代谢组学的影响研究显示,造模后线粒体与生物膜出现了较显著的改变,相应的代谢标志物在尿液中含量有所改变。阳性药物组有一定的回调作用,但脑力健各治疗组回调能力总体较差,但总体有一定的治疗作用。
结论：
1.脑力健具有改善A β海马注射痴呆模型学习记忆的作用,提示其具有良好的益智作用。
2.脑力健对A β海马注射导致的脑病理形态学改变具有保护作用。
3.脑力健有增强IDE活性的作用。
4.脑力健对模型cdk5和GSK-3的高表达有良好的抑制,提示其对痴呆tau蛋白过度或异常磷酸化形成神经元纤维缠结有抑制和／或拮抗作用；脑力健对模型海马突触素异常低表达有拮抗作用,可以提高海马CAl区突触素的表达水平,提示其具有促进神经突触重塑的作用。
5.AD损伤的过程包含了能量代谢与脂膜结构的异常,脑力健各治疗组回调能力总体较差,但有一定的治疗作用。
Alzheimer's disease(AD) is a degenerative diseases of the nervous system which is unknown reason, it's main pathological changes consist of the extensive nerve cells apoptosis, SP depositing, NFT and the nerve cells reducing. TCM compound NaoLiJian is protocoled according to the AD's pathogenesis of "ShenXuDuSun", and it has the effect of "BuShenJianNao, JieDuYiZhi". A β's neurotoxicity is a important factor in the happening and developing process of AD, and is also a hot target in the research of TCM resisting to AD in recent years. Metabolomics is one of the effective ways to evaluate the overall effect of TCM compound. This research has mainly studied that NaoLiJian how to influence the AD rats's learning and memory capacity, hippocampus morphology, hippocampus neurotoxicity and metabonomics, etc.
Objetive:
To explore NaoLiJian's relieving function to Aβ's neurotoxicity and it's mechanism, to reveals preliminarily the internal material and metabolic pathways change in the AD rats'body and NaoLiJian's intervention to the metabolic pathways.
Methods:
Using the agglomerate state of Aβ25-35to establish AD model by injecting in the rats'bilateral hippocampal. After drug intervening, using the Morris water maze to observe NaoLiJian's influence on the learning and memory capacity of AD rats, using pathological ways to watch it's influence on the brain morphology, using immunohistochemistry method to test IDE, cdk5, GSK-3, SYN expression and their average optical density in the hippocampal. Collecting metabolic product, after the steps of sample processing, testing, data processing, then to observe it's influence on the metabonomics.
Results:
1. Effects on function of learning and memory of AD rats
Place navigation show that the escape latency of the model group are significantly extended, and the latency of the drug groups are significantly shorter than the model group (P<0.05). Spatial probe test show that the stating in the first quadrant time and platform retention time of the model group shorten significantly, and the number of passing platform reduce remarkably; while the time of the drug groups spending are longer and the number are more than the model group (P<0.05)
2. Effects on brain pathology morphology
The results show that the most cases of the model group have appeared to nerve cells reduce in different degree, neuronal apoptosis and gliocytes hyperplasia, but the situation of the drug groups are significantly better than the model group.
3. Effects on IDE expression
The results show that the products of IDE positive immune response are strikingly low expression in the model control group, while the expression of NaoLiJian each dose groups are elevatory, medium dose group are obviously higher than the model group. The IDE average optic density of the model group are significantly lower than the blank control group (P<0.01), while its in treatment groups are significantly increased (P<0.05).
4. Effects on CDK5expression
The results show that the cdk5expression of the model group are obviously higher than the sham operation group, while NaoLiJian each dose groups are significantly lower than the model group. The cdk5average optic density in hippocampus of the model group are remarkably higher than the blank control group (P<0.01), while its in NaoLiJian each dose groups are significantly lower than the model group (P<0.05).
5. Effects on GSK-3expression
The results show that the products of GSK-3positive response can be seen in hippocampus CA1area after A β injecting, the GSK-3expression of the model group are strikingly more than the blank control group, while the expression both of NaoLiJian each dose groups and the sham operation group are significantly reduced. The average optic density of the model control group are obviously higher than the blank control group (P<0.01) this suggests that the GSK-3activity of the model group markedly enhanced; while its in NaoLiJian each dose groups are significantly reduced (P<0.01), but no significant differences between groups (P>0.05)
6. Effects on SYN expression
The results show that the SYN expression of the model group are remarkably lower than the sham operation group(P<0.05); while the all SYN expression of NaoLiJian groups are obviously higher than the model group (P<0.01). The average optic density of the model group are significantly lower than the sham operation group (P<0.01), while the all average optic density of NaoLiJian groups are markedly higher than the model group (P<0.05)
7. Effects on metabonomics
The results show that the mitochondria and biological membrane of AD rats have appeared significant change after establishing model, the content of corresponding metabolic markers in the urine have changed also. The positive drug group have certain callback function, but the callback ability of NaoLiJian groups are poor overall, total have certain curative effect merely.
Conclusion:
1. NaoLiJian has effect on improving AD rats'the capacity of learning and memory, this suggests that NaoLiJian can increase intelligence.
2. Aβcan induce brain pathology morphological change, while NaoLiJian has protective function on it.
3. NaoLijian has effect on enhancing IDE activity.
4. NaoLiJian has good suppressive effect on cdk5and GSK-3high expression of AD model, this prompt that it can inhibit and/or antagonize excessive or abnormal tau protein phosphorylation which can form neurons fiber tangles; NaoLiJian can improve the low expression level of SYN in the hippocampus, this prompt that it has the function on stimulating nerve synapsis remodeling.
5. The process of AD's damage include abnormal energy metabolism and lipid membrane structure, NaoLiJian's callback ability overall to these is poor, but it has certain curative effect.
目的：探讨脑力健对AD大鼠A β神经毒性的改善作用及其机制,初步揭示AD大鼠的体内物质变化和代谢途径变化以及脑力健对AD大鼠代谢途径的干预作用。
方法：用聚集状态的Aβ25-35大鼠双侧海马注射建立AD模型,药物干预后,Morris水迷宫观察脑力健对AD大鼠学习记忆能力的影响,病理观察脑力健对AD大鼠脑形态学的影响,用免疫组化的方法检测大鼠海马IDE、cdk5、GSK-3、SYN的表达和平均光密度,收集代谢产物后经过样本处理、测试、数据处理等步骤观察脑力健对AD大鼠代谢组学的影响。
结果：
1.脑力健对AD大鼠学习记忆功能的影响定位航行实验显示,模型对照组大鼠的逃避潜伏期均显著延长；给药各组与模型组比较,大鼠逃避潜伏期均显著缩短,有显著统计学意义(P<0.05)。空间探索实验显示模型组在第一象限时间和平台停留时间显著缩短,经过平台次数显著减少；而给药组第一象限时间和平台停留时间均较模型对照组显著延长、经过平台次数显著增多,有显著的统计学意义(P<0.05)。
2.脑力健对A β海马注射痴呆模型脑病理形态学的影响结果显示,模型纽多数病例不同程度神经细胞减少,神经元凋亡及胶质细胞增生；给药组较模型对照组其神经细胞凋亡、CA1区水肿、胶质细胞增生等情况均显著减轻。
3.脑力健对A β海马注射痴呆模型Aβ降解酶IDE表达的影响研究表明,模型对照组IDE阳性免疫反应产物呈显著低表达,脑力健高、中剂量组较模型对照组阳性表达显著增高。模型对照组海马区IDE平均光密度值较空白对照组显著降低(P<0.01),脑力健各剂量组与模型对照组比较则显著增高(P<0.05)
4.脑力健对A β注射痴呆鼠海马区CDK5表达的影响研究表明,模型组较假手术组其cdk5有显著高表达,脑力健各组cdk5的表达均明显低于模型组。模型组海马区的cdk5平均光密度值较空白对照组显著增高(P<0.01),脑力健各给药组与模型对照组比较显著降低,有显著的统计学意义(P<0.05)。
5.脑力健对A β注射痴呆鼠海马区GSK-3表达的影响研究显示,A β海马注射后各组大鼠海马CA1区均可见GSK-3的阳性反应物,模型组GSK-3表达较假手术组明显增多,脑力健各剂量组染色结果与假手术组相似,表达显著减少；模型对照组海马区平均光密度值较空白对照组显著增高(P<0.01),提示模型组海马GSK-3活性显著增强；脑力健各组与模型对照组GSK-3的平均光密度比较则显著降低(P<0.01),但组间无显著差异(P>0.05)
6.脑力健对A β注射痴呆鼠海马区SYN表达的影响研究显示,假手术组的SYN表达高于模型组,差异具有显著性(P<0.05)；脑力健各给药组海马区突出素的表达均明显高于模型组(P<0.01)。模型对照组海马区SYN平均光密度值较假手术组显著降低(P<0.01),脑力键高、中、低剂量组与模型对照组比较,平均光密度值显著增高(P<0.05)。
7.脑力健对A β注射痴呆鼠代谢组学的影响研究显示,造模后线粒体与生物膜出现了较显著的改变,相应的代谢标志物在尿液中含量有所改变。阳性药物组有一定的回调作用,但脑力健各治疗组回调能力总体较差,但总体有一定的治疗作用。
结论：
1.脑力健具有改善A β海马注射痴呆模型学习记忆的作用,提示其具有良好的益智作用。
2.脑力健对A β海马注射导致的脑病理形态学改变具有保护作用。
3.脑力健有增强IDE活性的作用。
4.脑力健对模型cdk5和GSK-3的高表达有良好的抑制,提示其对痴呆tau蛋白过度或异常磷酸化形成神经元纤维缠结有抑制和／或拮抗作用；脑力健对模型海马突触素异常低表达有拮抗作用,可以提高海马CAl区突触素的表达水平,提示其具有促进神经突触重塑的作用。
5.AD损伤的过程包含了能量代谢与脂膜结构的异常,脑力健各治疗组回调能力总体较差,但有一定的治疗作用。
Alzheimer's disease(AD) is a degenerative diseases of the nervous system which is unknown reason, it's main pathological changes consist of the extensive nerve cells apoptosis, SP depositing, NFT and the nerve cells reducing. TCM compound NaoLiJian is protocoled according to the AD's pathogenesis of "ShenXuDuSun", and it has the effect of "BuShenJianNao, JieDuYiZhi". A β's neurotoxicity is a important factor in the happening and developing process of AD, and is also a hot target in the research of TCM resisting to AD in recent years. Metabolomics is one of the effective ways to evaluate the overall effect of TCM compound. This research has mainly studied that NaoLiJian how to influence the AD rats's learning and memory capacity, hippocampus morphology, hippocampus neurotoxicity and metabonomics, etc.
Objetive:
To explore NaoLiJian's relieving function to Aβ's neurotoxicity and it's mechanism, to reveals preliminarily the internal material and metabolic pathways change in the AD rats'body and NaoLiJian's intervention to the metabolic pathways.
Methods:
Using the agglomerate state of Aβ25-35to establish AD model by injecting in the rats'bilateral hippocampal. After drug intervening, using the Morris water maze to observe NaoLiJian's influence on the learning and memory capacity of AD rats, using pathological ways to watch it's influence on the brain morphology, using immunohistochemistry method to test IDE, cdk5, GSK-3, SYN expression and their average optical density in the hippocampal. Collecting metabolic product, after the steps of sample processing, testing, data processing, then to observe it's influence on the metabonomics.
Results:
1. Effects on function of learning and memory of AD rats
Place navigation show that the escape latency of the model group are significantly extended, and the latency of the drug groups are significantly shorter than the model group (P<0.05). Spatial probe test show that the stating in the first quadrant time and platform retention time of the model group shorten significantly, and the number of passing platform reduce remarkably; while the time of the drug groups spending are longer and the number are more than the model group (P<0.05)
2. Effects on brain pathology morphology
The results show that the most cases of the model group have appeared to nerve cells reduce in different degree, neuronal apoptosis and gliocytes hyperplasia, but the situation of the drug groups are significantly better than the model group.
3. Effects on IDE expression
The results show that the products of IDE positive immune response are strikingly low expression in the model control group, while the expression of NaoLiJian each dose groups are elevatory, medium dose group are obviously higher than the model group. The IDE average optic density of the model group are significantly lower than the blank control group (P<0.01), while its in treatment groups are significantly increased (P<0.05).
4. Effects on CDK5expression
The results show that the cdk5expression of the model group are obviously higher than the sham operation group, while NaoLiJian each dose groups are significantly lower than the model group. The cdk5average optic density in hippocampus of the model group are remarkably higher than the blank control group (P<0.01), while its in NaoLiJian each dose groups are significantly lower than the model group (P<0.05).
5. Effects on GSK-3expression
The results show that the products of GSK-3positive response can be seen in hippocampus CA1area after A β injecting, the GSK-3expression of the model group are strikingly more than the blank control group, while the expression both of NaoLiJian each dose groups and the sham operation group are significantly reduced. The average optic density of the model control group are obviously higher than the blank control group (P<0.01) this suggests that the GSK-3activity of the model group markedly enhanced; while its in NaoLiJian each dose groups are significantly reduced (P<0.01), but no significant differences between groups (P>0.05)
6. Effects on SYN expression
The results show that the SYN expression of the model group are remarkably lower than the sham operation group(P<0.05); while the all SYN expression of NaoLiJian groups are obviously higher than the model group (P<0.01). The average optic density of the model group are significantly lower than the sham operation group (P<0.01), while the all average optic density of NaoLiJian groups are markedly higher than the model group (P<0.05)
7. Effects on metabonomics
The results show that the mitochondria and biological membrane of AD rats have appeared significant change after establishing model, the content of corresponding metabolic markers in the urine have changed also. The positive drug group have certain callback function, but the callback ability of NaoLiJian groups are poor overall, total have certain curative effect merely.
Conclusion:
1. NaoLiJian has effect on improving AD rats'the capacity of learning and memory, this suggests that NaoLiJian can increase intelligence.
2. Aβcan induce brain pathology morphological change, while NaoLiJian has protective function on it.
3. NaoLijian has effect on enhancing IDE activity.
4. NaoLiJian has good suppressive effect on cdk5and GSK-3high expression of AD model, this prompt that it can inhibit and/or antagonize excessive or abnormal tau protein phosphorylation which can form neurons fiber tangles; NaoLiJian can improve the low expression level of SYN in the hippocampus, this prompt that it has the function on stimulating nerve synapsis remodeling.
5. The process of AD's damage include abnormal energy metabolism and lipid membrane structure, NaoLiJian's callback ability overall to these is poor, but it has certain curative effect.
引文
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