中药复方有效组分对APP转基因小鼠学习记忆的影响及其作用机理研究
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摘要
老年性痴呆又称阿尔茨海默病(Alzheimer's disease, AD),是一种常见的以进行性认知功能减退为特征的中枢神经系统变性疾病。随着全球人口的老龄化,AD的发病率呈不断上升趋势,但迄今为止,AD作为一个世界医学难题,其发病机制尚不十分清楚,理想的治疗手段和药物仍然缺乏。中医根据辨证论治,尤其是充分发挥中药复方多途径、多环节、多靶点、多向调节的作用特点,在防治AD方面具有优势和前景。还脑益聪方是基于中医AD“虚-瘀-浊-毒”病机的中药复方,经前期临床和实验研究证实对AD有较好的防治作用,现应用现代工艺技术提取其有效组分,进一步研究本方对AD动物模型的作用机理和效应途径,为临床治疗AD提供依据。
目的：
基于AD发病机理中的“Aβ级联学说”,研究中药复方还脑益聪方有效组分对AD动物模型脑组织Aβ生成途径及炎症反应和氧化应激相关指标的影响,探讨还脑益聪方治疗AD的作用机理。
方法：
选用3月龄APP695V717I转基因小鼠AD模型,随机分为模型组、盐酸多奈哌齐组、还脑益聪方有效组分大剂量组和小剂量组,并设立正常对照组(C57BL/6J小鼠),连续灌胃6个月后进行相关指标检测。本实验共分为三个部分。第一部分,采用Morris水迷宫观测APP转基因小鼠空间学习记忆能力,采用跳台实验观测小鼠一次性被动回避反应记忆功能,研究还脑益聪方对APP转基因小鼠行为学的影响。第二部分,采用免疫组织化学法检测APP转基因小鼠脑组织APP、BACE和Aβ等蛋白表达水平,采用刚果红染色观察小鼠脑组织淀粉样沉积的变化,研究还脑益聪方对APP转基因小鼠脑组织Ap生成途径的影响。第三部分,采用免疫组织化学法检测APP转基因小鼠脑组织AD免疫炎症相关核转录因子NF-κB、PPARγ的表达水平,采用放射免疫法检测APP转基因小鼠脑组织皮层和海马的炎症因子IL-6、hs-CRP的含量；采用双缩脲法测定APP转基因小鼠皮层、海马的总蛋白含量；采用比色法检测APP转基因小鼠血清SOD活性,采用硫代巴比妥酸法测定小鼠血清MDA含量,研究还脑益聪方对APP转基因小鼠脑内炎症因子和氧化应激的影响。
结果：
第一部分,还脑益聪方对APP转基因小鼠行为学的影响。行为学实验表明,还脑益聪方组和盐酸多奈哌齐组小鼠在Morris水迷宫中穿越原平台位置次数均较模型组显著增多(P<0.05),在原平台所在第四象限游泳时间和游泳路程亦均较模型组显著延长(P<0.05或P<0.01)。各给药组小鼠在跳台实验中的错误次数与模型组比较无显著性差异(P>0.05),还脑益聪方大剂量组和盐酸多奈哌齐组小鼠潜伏期较模型组显著延长(P<0.01或P<0.05),还脑益聪方小剂量组小鼠潜伏期亦有延长趋势,但较模型组无显著性差异(P>0.05)。
第二部分,还脑益聪方对APP转基因小鼠脑组织Ap生成途径的影响。还脑益聪方组和盐酸多奈哌齐组小鼠海马CA1区APP阳性细胞数目和面积比例较模型组均显著减少(P<0.01)；还脑益聪方组小鼠海马CA1区BACE阳性细胞数目较模型组显著减少(P<0.01),盐酸多奈哌齐组较模型组亦有所减少,但无显著性差异(P>0.05)；各给药组小鼠海马CA1区Ap阳性细胞数目和面积比例较模型组均显著减少(P<0.05或P<0.01)。刚果红染色发现,模型组小鼠在皮层及海马均出现散在分布的橘红色沉积物,大小不一、染色不均,其中海马体部分布较为密集；与模型组比较,还脑益聪方组和盐酸多奈哌齐组小鼠脑组织橘红色染色比较局限,染色较浅,数目明显减少。
第三部分,还脑益聪方对APP转基因小鼠脑组织炎症因子和氧化应激的影响。还脑益聪方组和盐酸多奈哌齐组小鼠治疗后,海马CA1区NF-κB阳性细胞数目较模型组显著减少(P<0.05或P<0.01),PPARy阳性细胞数目较模型组显著增多(P<0.05)；脑组织IL-6的含量比较,还脑益聪方组小鼠皮层IL-6的含量较模型组显著减少(P<0.05或P<0.01),盐酸多奈哌齐组小鼠皮层IL-6的含量较模型组亦有所减少,但无显著性差异(P>0.05),还脑益聪方小剂量组和盐酸多奈哌齐组小鼠海马IL-6的含量较模型组显著减少(P<0.05),还脑益聪方大剂量组小鼠海马IL-6的含量较模型组亦有所减少,但无显著性差异(P>0.05)；脑组织hs-CRP的含量比较,各给药组小鼠海马和皮层的hs-CRP含量较模型组均呈减少趋势,但无显著性差异(P>0.05)。还脑益聪方组小鼠血清SOD活性较模型组显著升高(P<0.05或P<0.01),盐酸多奈哌齐组小鼠血清SOD活性与模型组比较无显著性差异(P>0.05)；各给药组小鼠血清MDA含量与模型组比较无显著性差异(P>0.05)。
结论：
还脑益聪方有效组分可以明显改善APP转基因小鼠空间学习记忆能力和-次性被动回避反应记忆功能；还脑益聪方有效组分可以通过下调APP转基因小鼠脑组织APP及其p分泌酶的表达,减少Ap的生成和聚集,减少脑内淀粉样沉积的形成；还脑益聪方有效组分可以上调APP转基因小鼠脑组织炎症相关核转录因子PPARγ的表达,抑制NF-κB的表达,降低脑组织炎症因子的含量,减轻炎症反应；还脑益聪方有效组分对APP转基因小鼠的血清氧自由基清除能力有显著提高作用,能减轻氧化应激反应。本研究提示用还脑益聪方治疗APP转基因小鼠AD模型,可以减轻小鼠脑内Aβ的神经毒性及其诱导的炎症反应和氧化应激,改善其学习记忆能力,提示还脑益聪方对AD的治疗具有多作用靶点,可以通过抗Ap神经毒性、抗炎、抗氧化的作用途径防治AD。
Alzheimer's disease (AD) is a common neurodegenerative disease, characterized by progressive cognitive function deterioration. As the aging of human beings in the world, the incidence of AD is increasingly high. But so far, as a world medical problem, the pathogenesis of AD has not been clear, and its ideal drug treatment has still been deficient. The treatment of Traditional Chinese Medicine (TCM), based on syndrome differentiation, has superiority and prospect at the prevention and treatment of AD, especially by the role of Chinese herbal compound, which has many curative pathways and targets to AD. Huannao Yicong Fang (HNYCF) is a Chinese herbal compound based on "Deficiency-Blood Stasis-Turbidity-Toxin", the pathogenesis of AD in TCM. It has been proved that HNYCF has good preventive and therapeutic effects to AD. Now, we use modern technology to extract the effective fractions of HNYCF, and study further its mechanism and effective channel to AD animal model, so as to provide basis to the clinical treatment of AD.
Objective:
According to beta-amyloid cascade hypothesis in AD, this study is to observe effects of the effective fractions of HNYCF (herbal extract) on generation of beta amyloid protein (Aβ), inflammatory and oxidative stress in the brain of AD animal model, to explore the mechanism of HNYCF in the treating of AD.
Methods:
APP695V717I transgenic mice 3 month-old were used as AD models in this study, which were randomly divided into model group, Donepezil group, HNYCF large dose group and HNYCF small dose group. Normal control adopted the same age and background C57BL/6J mice. The animals were administered intragastrically by the drug or water from 3 month-old to 9 month-old. This research was divided into three parts. PartⅠ:Morris water maze test was performed to measure the spatial learning and memory ability. Step-down test was performed to observe the learning and memory ability of single passive avoidance response. This part was to study effects of HNYCF on the behavior of APP transgenic mice. PartⅡ:The expression ofβ-amyloid precursor protein (APP),β-site APP cleaving enzyme (BACE) and Aβin hippocampus CA1 region was detected by immunohistochemistry with image analysis. Amyloid deposition were observed with Congo red staining. This part was to study effects of HNYCF on generation of Aβin the brain of APP transgenic mice. PartⅢ: The expression of nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptorγ(PPARγ) in hippocampus CA1 region were detected by immunohistochemistry with image analysis. The content of inflammatory cytokines interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP) in the brain cortex and hippocampus homogenate were detected with radioimmunoassay (RIA). The content of total protein in the brain cortex and hippocampus homogenate was detected with biuret method. The activity of superoxide dismutase (SOD) in serum was detected with colorimetry. The content of malondialdehyde (MDA) in serum was detected with Thibabituric Acid (TBA). This part was to study effects of HNYCF on inflammatory cytokines and oxidative stress in the brain of APP transgenic mice.
Results:
PartⅠ:Behavioral experiments suggested the effects of HNYCF on the behavior of APP transgenic mice. Morris water maze test showed that the times of crossing platform of HNYCF group and Donepezil group were much more than that in the model group (P＜0.05), the swimming time and distance of all treated groups in the fourth quadrant where the original platform put were prolonged distinctly (P< 0.05 or P<0.01). The mice step-down test manifested that there was no statistical significant difference about wrong times among all treated groups and the model group (P>0.05), but the escape latency of HNYCF large dose group and Donepezil group was significantly longer than model group (P<0.05 or P<0.01), and the escape latency of HNYCF small dose group had the trend of extension but had no statistical significant difference comparing to the model group (P>0.05).
PartⅡ:Comparing to the model group, the levels of expression of APP in hippocampus CA1 region of mice in the HNYCF group and Donepezil group decreased obviously (P<0.01), including its number and area proportion of positive cells. Comparing to the model group, the number of positive cells of BACE in the HNYCF group decreased significantly (P<0.01), and Donepezil group had the trend to reduce, but there was no statistical significant difference (P>0.05). The expression of Aβin hippocampus CA1 region of mice in all the treated groups decreased obviously (P＜0.05 or P<0.01), comparing with model group. Congo red staining showed that there were orange deposition scattered in the cortex and hippocampus of mice in the model group, which had sizes, uneven coloring, and intensively in the hippocampus. Comparing to the model group, HNYCF group and Donepezil group had shallow and limited orange staining, and its number decreased significantly.
Part III:After treated with HNYCF and Donepezil, the number of NF-κB positive cells in hippocampus CA1 region in the APP transgenic mice decreased obviously (P<0.05 or P<0.01), comparing to the model group. The number of PPARy positive cells increased significantly in the brain of mice in all treated groups (P<0.05). The content of IL-6 in the brain cortex in HNYCF group was lower than that of model group (P<0.05 or P<0.01), and that in Donepezil group was also decreased, but not significantly different (P>0.05). Comparing with the model group, the content of IL-6 in hippocampus in HNYCF small dose group and Donepezil group decreased obviously (P<0.05), and which was in HNYCF large dose group also reduced, but there was no significant difference (P>0.05). Comparing the content of hs-CRP in the brain tissue, there was no significant difference among all treated groups and the model group (P>0.05), but all the treated groups had the trend of reduction. The activity of SOD in serum of HNYCF group was significantly higher than model group (P<0.05 or P<0.01), but there was no siginificant difference between Donepezil group and model group (P>0.05). Comparing the content of MDA in serum, there was no significant difference among all treated groups and the model group (P>0.05).
Conclusions:
The effective fractions of HNYCF can ameliorate evidently the spatial learning and memory ability and that of single passive avoidance response of APP transgenic mice. The effective fractions of HNYCF can decrease the expression of APP and itsβ-secretase, reduce the production and accumulation of Aβ, and reduce the amyloid deposition in the brain of APP transgenic mice. The effective fractions of HNYCF can increase the expression of PPARy, inhibit the expression of NF-κB, decrease the content of inflammatory cytokines, and alleviate inflammatory response in the brain of APP transgenic mice. The effective fractions of HNYCF can also improve the ability of scavenging oxygen free radicals, alleviate oxidative stress in APP transgenic mice. This study suggests that HNYCF can reduce the neuron toxicity of Aβin the brain of APP transgenic mice, alleviate the induced inflammatory response and oxidative stress, and improve their learning and memory ability. Briefly, this study suggests HNYCF has many effective targets in treating AD, can prevent and treat AD by anti-Aβneurotoxicity, anti-inflammatory and anti-oxidation.
目的：
基于AD发病机理中的“Aβ级联学说”,研究中药复方还脑益聪方有效组分对AD动物模型脑组织Aβ生成途径及炎症反应和氧化应激相关指标的影响,探讨还脑益聪方治疗AD的作用机理。
方法：
选用3月龄APP695V717I转基因小鼠AD模型,随机分为模型组、盐酸多奈哌齐组、还脑益聪方有效组分大剂量组和小剂量组,并设立正常对照组(C57BL/6J小鼠),连续灌胃6个月后进行相关指标检测。本实验共分为三个部分。第一部分,采用Morris水迷宫观测APP转基因小鼠空间学习记忆能力,采用跳台实验观测小鼠一次性被动回避反应记忆功能,研究还脑益聪方对APP转基因小鼠行为学的影响。第二部分,采用免疫组织化学法检测APP转基因小鼠脑组织APP、BACE和Aβ等蛋白表达水平,采用刚果红染色观察小鼠脑组织淀粉样沉积的变化,研究还脑益聪方对APP转基因小鼠脑组织Ap生成途径的影响。第三部分,采用免疫组织化学法检测APP转基因小鼠脑组织AD免疫炎症相关核转录因子NF-κB、PPARγ的表达水平,采用放射免疫法检测APP转基因小鼠脑组织皮层和海马的炎症因子IL-6、hs-CRP的含量；采用双缩脲法测定APP转基因小鼠皮层、海马的总蛋白含量；采用比色法检测APP转基因小鼠血清SOD活性,采用硫代巴比妥酸法测定小鼠血清MDA含量,研究还脑益聪方对APP转基因小鼠脑内炎症因子和氧化应激的影响。
结果：
第一部分,还脑益聪方对APP转基因小鼠行为学的影响。行为学实验表明,还脑益聪方组和盐酸多奈哌齐组小鼠在Morris水迷宫中穿越原平台位置次数均较模型组显著增多(P<0.05),在原平台所在第四象限游泳时间和游泳路程亦均较模型组显著延长(P<0.05或P<0.01)。各给药组小鼠在跳台实验中的错误次数与模型组比较无显著性差异(P>0.05),还脑益聪方大剂量组和盐酸多奈哌齐组小鼠潜伏期较模型组显著延长(P<0.01或P<0.05),还脑益聪方小剂量组小鼠潜伏期亦有延长趋势,但较模型组无显著性差异(P>0.05)。
第二部分,还脑益聪方对APP转基因小鼠脑组织Ap生成途径的影响。还脑益聪方组和盐酸多奈哌齐组小鼠海马CA1区APP阳性细胞数目和面积比例较模型组均显著减少(P<0.01)；还脑益聪方组小鼠海马CA1区BACE阳性细胞数目较模型组显著减少(P<0.01),盐酸多奈哌齐组较模型组亦有所减少,但无显著性差异(P>0.05)；各给药组小鼠海马CA1区Ap阳性细胞数目和面积比例较模型组均显著减少(P<0.05或P<0.01)。刚果红染色发现,模型组小鼠在皮层及海马均出现散在分布的橘红色沉积物,大小不一、染色不均,其中海马体部分布较为密集；与模型组比较,还脑益聪方组和盐酸多奈哌齐组小鼠脑组织橘红色染色比较局限,染色较浅,数目明显减少。
第三部分,还脑益聪方对APP转基因小鼠脑组织炎症因子和氧化应激的影响。还脑益聪方组和盐酸多奈哌齐组小鼠治疗后,海马CA1区NF-κB阳性细胞数目较模型组显著减少(P<0.05或P<0.01),PPARy阳性细胞数目较模型组显著增多(P<0.05)；脑组织IL-6的含量比较,还脑益聪方组小鼠皮层IL-6的含量较模型组显著减少(P<0.05或P<0.01),盐酸多奈哌齐组小鼠皮层IL-6的含量较模型组亦有所减少,但无显著性差异(P>0.05),还脑益聪方小剂量组和盐酸多奈哌齐组小鼠海马IL-6的含量较模型组显著减少(P<0.05),还脑益聪方大剂量组小鼠海马IL-6的含量较模型组亦有所减少,但无显著性差异(P>0.05)；脑组织hs-CRP的含量比较,各给药组小鼠海马和皮层的hs-CRP含量较模型组均呈减少趋势,但无显著性差异(P>0.05)。还脑益聪方组小鼠血清SOD活性较模型组显著升高(P<0.05或P<0.01),盐酸多奈哌齐组小鼠血清SOD活性与模型组比较无显著性差异(P>0.05)；各给药组小鼠血清MDA含量与模型组比较无显著性差异(P>0.05)。
结论：
还脑益聪方有效组分可以明显改善APP转基因小鼠空间学习记忆能力和-次性被动回避反应记忆功能；还脑益聪方有效组分可以通过下调APP转基因小鼠脑组织APP及其p分泌酶的表达,减少Ap的生成和聚集,减少脑内淀粉样沉积的形成；还脑益聪方有效组分可以上调APP转基因小鼠脑组织炎症相关核转录因子PPARγ的表达,抑制NF-κB的表达,降低脑组织炎症因子的含量,减轻炎症反应；还脑益聪方有效组分对APP转基因小鼠的血清氧自由基清除能力有显著提高作用,能减轻氧化应激反应。本研究提示用还脑益聪方治疗APP转基因小鼠AD模型,可以减轻小鼠脑内Aβ的神经毒性及其诱导的炎症反应和氧化应激,改善其学习记忆能力,提示还脑益聪方对AD的治疗具有多作用靶点,可以通过抗Ap神经毒性、抗炎、抗氧化的作用途径防治AD。
Alzheimer's disease (AD) is a common neurodegenerative disease, characterized by progressive cognitive function deterioration. As the aging of human beings in the world, the incidence of AD is increasingly high. But so far, as a world medical problem, the pathogenesis of AD has not been clear, and its ideal drug treatment has still been deficient. The treatment of Traditional Chinese Medicine (TCM), based on syndrome differentiation, has superiority and prospect at the prevention and treatment of AD, especially by the role of Chinese herbal compound, which has many curative pathways and targets to AD. Huannao Yicong Fang (HNYCF) is a Chinese herbal compound based on "Deficiency-Blood Stasis-Turbidity-Toxin", the pathogenesis of AD in TCM. It has been proved that HNYCF has good preventive and therapeutic effects to AD. Now, we use modern technology to extract the effective fractions of HNYCF, and study further its mechanism and effective channel to AD animal model, so as to provide basis to the clinical treatment of AD.
Objective:
According to beta-amyloid cascade hypothesis in AD, this study is to observe effects of the effective fractions of HNYCF (herbal extract) on generation of beta amyloid protein (Aβ), inflammatory and oxidative stress in the brain of AD animal model, to explore the mechanism of HNYCF in the treating of AD.
Methods:
APP695V717I transgenic mice 3 month-old were used as AD models in this study, which were randomly divided into model group, Donepezil group, HNYCF large dose group and HNYCF small dose group. Normal control adopted the same age and background C57BL/6J mice. The animals were administered intragastrically by the drug or water from 3 month-old to 9 month-old. This research was divided into three parts. PartⅠ:Morris water maze test was performed to measure the spatial learning and memory ability. Step-down test was performed to observe the learning and memory ability of single passive avoidance response. This part was to study effects of HNYCF on the behavior of APP transgenic mice. PartⅡ:The expression ofβ-amyloid precursor protein (APP),β-site APP cleaving enzyme (BACE) and Aβin hippocampus CA1 region was detected by immunohistochemistry with image analysis. Amyloid deposition were observed with Congo red staining. This part was to study effects of HNYCF on generation of Aβin the brain of APP transgenic mice. PartⅢ: The expression of nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptorγ(PPARγ) in hippocampus CA1 region were detected by immunohistochemistry with image analysis. The content of inflammatory cytokines interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP) in the brain cortex and hippocampus homogenate were detected with radioimmunoassay (RIA). The content of total protein in the brain cortex and hippocampus homogenate was detected with biuret method. The activity of superoxide dismutase (SOD) in serum was detected with colorimetry. The content of malondialdehyde (MDA) in serum was detected with Thibabituric Acid (TBA). This part was to study effects of HNYCF on inflammatory cytokines and oxidative stress in the brain of APP transgenic mice.
Results:
PartⅠ:Behavioral experiments suggested the effects of HNYCF on the behavior of APP transgenic mice. Morris water maze test showed that the times of crossing platform of HNYCF group and Donepezil group were much more than that in the model group (P＜0.05), the swimming time and distance of all treated groups in the fourth quadrant where the original platform put were prolonged distinctly (P< 0.05 or P<0.01). The mice step-down test manifested that there was no statistical significant difference about wrong times among all treated groups and the model group (P>0.05), but the escape latency of HNYCF large dose group and Donepezil group was significantly longer than model group (P<0.05 or P<0.01), and the escape latency of HNYCF small dose group had the trend of extension but had no statistical significant difference comparing to the model group (P>0.05).
PartⅡ:Comparing to the model group, the levels of expression of APP in hippocampus CA1 region of mice in the HNYCF group and Donepezil group decreased obviously (P<0.01), including its number and area proportion of positive cells. Comparing to the model group, the number of positive cells of BACE in the HNYCF group decreased significantly (P<0.01), and Donepezil group had the trend to reduce, but there was no statistical significant difference (P>0.05). The expression of Aβin hippocampus CA1 region of mice in all the treated groups decreased obviously (P＜0.05 or P<0.01), comparing with model group. Congo red staining showed that there were orange deposition scattered in the cortex and hippocampus of mice in the model group, which had sizes, uneven coloring, and intensively in the hippocampus. Comparing to the model group, HNYCF group and Donepezil group had shallow and limited orange staining, and its number decreased significantly.
Part III:After treated with HNYCF and Donepezil, the number of NF-κB positive cells in hippocampus CA1 region in the APP transgenic mice decreased obviously (P<0.05 or P<0.01), comparing to the model group. The number of PPARy positive cells increased significantly in the brain of mice in all treated groups (P<0.05). The content of IL-6 in the brain cortex in HNYCF group was lower than that of model group (P<0.05 or P<0.01), and that in Donepezil group was also decreased, but not significantly different (P>0.05). Comparing with the model group, the content of IL-6 in hippocampus in HNYCF small dose group and Donepezil group decreased obviously (P<0.05), and which was in HNYCF large dose group also reduced, but there was no significant difference (P>0.05). Comparing the content of hs-CRP in the brain tissue, there was no significant difference among all treated groups and the model group (P>0.05), but all the treated groups had the trend of reduction. The activity of SOD in serum of HNYCF group was significantly higher than model group (P<0.05 or P<0.01), but there was no siginificant difference between Donepezil group and model group (P>0.05). Comparing the content of MDA in serum, there was no significant difference among all treated groups and the model group (P>0.05).
Conclusions:
The effective fractions of HNYCF can ameliorate evidently the spatial learning and memory ability and that of single passive avoidance response of APP transgenic mice. The effective fractions of HNYCF can decrease the expression of APP and itsβ-secretase, reduce the production and accumulation of Aβ, and reduce the amyloid deposition in the brain of APP transgenic mice. The effective fractions of HNYCF can increase the expression of PPARy, inhibit the expression of NF-κB, decrease the content of inflammatory cytokines, and alleviate inflammatory response in the brain of APP transgenic mice. The effective fractions of HNYCF can also improve the ability of scavenging oxygen free radicals, alleviate oxidative stress in APP transgenic mice. This study suggests that HNYCF can reduce the neuron toxicity of Aβin the brain of APP transgenic mice, alleviate the induced inflammatory response and oxidative stress, and improve their learning and memory ability. Briefly, this study suggests HNYCF has many effective targets in treating AD, can prevent and treat AD by anti-Aβneurotoxicity, anti-inflammatory and anti-oxidation.
引文
[1]Glenner GG, Wong CW. Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J]. Biochem Biophys Res Commun,1984,120(3):885-890.
[2]Kang J, Lemaire HG, Unterbeck A, et al.The precursor of Alzheimer's disease amyloidA4 protein resembles a cell-surface receptor[J]. Nature,1987,325(6106):733-736.
[3]刘元,华茜,雷洪涛,等.老年斑p淀粉样蛋白的清除机制[J].现代生物医学进展,2008,8(1)：152-154.
[4]Hooper C, Fry VA, Sevastou IG, et al. Scavenger receptor control of chromogranin A-induced microglial stress and neurotoxic cascades[J]. FEBS Lett,2009,583(21):3461-3466.
[5]Shepherd C, McCann H, Halliday GM. Variations in the neuropathology of familial Alzheimer's disease[J]. Acta Neuropathol,2009,118(1):37-52.
[6]Li M, Chen LY, Lee D, et al. The role of intracellular amyloid beta in Alzheimer's disease[J]. Prog Neurobiol,2007,83:131-139.
[7]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[8]Pimplikar SW. Reassessing the amyloid cascade hypothesis of Alzheimer's disease[J]. Int J Biochem Cell Biol,2009,41:1261-1268.
[9]Sotthibundhu A, Sykes AM, Fox B, et al. Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor[J]. J Neurosci,2008,28(15):3941-3946.
[10]Dong Y, Zhang G, Zhang B, et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels[J]. Arch Neurol,2009,66(5):620-631.
[11]Frasca G, Carbonaro V, Merlo S, et al. Integrins mediate beta-amyloid-induced cell-cycle activation and neuronal death[J]. J Neurosci Res,2008,86(2):350-355.
[12]谢朝阳,祝其锋,吴斌华.Ap25-35对PC12细胞周期及P21、CDK4、E2F1、BAX基因表达的影响[J].基础医学与临床,2009,29(4)：383-387.
[13]Cao X, Wei Z, Gabriel GG, et al. Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures:implications for
Alzheimer disease-related pathology[J]. BMC Neuroscience,2007,8(1):73.
[14]Puzzo D, Vitolo O, Trinchese F, et al. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity[J]. J Neurosci,2005,25(29):6887-6897.
[15]Lee JW, Lee YK, Yuk DY, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation[J]. J Neuroinflamm, 2008,29(5):37.
[16]蔡志友.小胶质细胞与阿尔茨海默病神经炎症[J].重庆医学,2008,37(7)：735-737.
[17]蔡志友.星形胶质细胞与阿尔茨海默病[J].重庆医学,2009,38(6)：733-735.
[18]杨小慧,姜招峰.小胶质细胞在阿尔茨海默病中的作用[J].生命的化学,2008,28(4)：431-433.
[19]Block ML, Hong JS. Chronic microglial activation and progressive dopaminergic neurotoxicity[J]. Biochem Soc Trans,2007,35(5):1127-1132.
[20]潘晓东,陈晓春,朱元贵,等.寡聚态β-淀粉样肽1-42可通过胶质-炎症反应损伤神经元[J].解剖学报,2008,39(6)：804-809.
[21]Walter S, Letiembre M, Liu Y, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease[J]. Cell Physiol Biochem,2007,20(6):947-956.
[22]Jin JJ, Kim HD, Maxwell JA, et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease[J]. J Neuroinflammation,2008,5:23-33.
[23]Farfara D, Lifshitz V, Frenkel D. Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease[J]. Cell Mol Med,2008,12(3):762-780.
[24]Sokolova A, Hill MD, Rahimi F, et al. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease[J]. Brain Pathol,2009, 19(3):392-398.
[25]Zhou J, Fonseca MI, Pisalyaput K, et al. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease[J]. J Neurochem,2008,106(5):2080.
[26]Granic I, Dolga AM, Nijholt IM, et al. Inflammation and NF-κB in Alzheimer's Disease and Diabetes[J]. Journal of Alzheimer's Disease,2009,16:809-821.
[27]Paris D, Patel N, Quadros A, et al. Inhibition of Abeta production by NF-kappaB inhibitors[J]. Neurosci Lett,2007,415(1):11-16.
[28]Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in beta-amyloid-treated C6 glioma cells[J]. Int J Mol Med, 2006,17(6):1069-1075.
[29]龚云涛,王晓民NF-κB与中枢神经系统退变性疾病[J].生命科学,2004,16(5)：280-283.
[30]冯梅,王奇,陈云波.核因子κB与胶质细胞在阿尔茨海默病中的研究进展[J].中国老年学杂志,2005,25(4)：484.
[31]Yang Y, Zhang EM, Zheng XX. Inducible nitric oxide synthase and NFκB signaling in amyloid (3-peptide induced neuron death and apoptosis[J]. Chin J Neuromed,2005,4(3): 295-299.
[32]Choi S, Kim JH, Roh EJ, et al. Nuclear factor-kappaB activated by capacitative Ca2+entry enhances muscarinic receptor-mediated soluble amyloid precursor protein (sAPPalpha) release in SH-SY5Y cells[J]. J Biol Chem,2006,281 (18):12722-12728.
[33]Heneka MT, Landreth GE. PPARs in the brain[J]. Biochimica et Biophysica Acta,2007,1771: 1031-1045.
[34]Bookout AL, Jeong Y, Downes M, et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network[J]. Cell 2006,126 (4):789-799.
[35]Victor NA, Wanderi EW, Gamboa J, et al. Altered PPARy expression and activation after transient focal ischemia in rats[J]. Eur J Neurosci 2006,24(6):1653-1663.
[36]de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease[J]. J Alzheimer's Dis,2006,9(2):167-181.
[37]Jiang QG, Heneka M, Landreth GE. The Role of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) in Alzheimer's Disease[J]. CNS Drugs,2008,22(1):1-14.
[38]Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPAR gamma[J]. Proc Natl Acad Sci USA,2006,103(2):443-448.
[39]Cristina D'ABRAMO, Sara MASSONE, Jean-Marc ZINGG, et al. Role of peroxisome proliferator-activated receptory in amyloid precursor protein processing and amyloid (3-mediated cell death[J]. Biochem,2005,391:693-698.
[40]Du J, Sun B, Chen K, et al. Antagonist of peroxisome proliferator-activated receptor y induces cerebellar amyloid-β levels and motor dysfunction in APP/PS1 transgenic mice[J].
Biochemical and Biophysical Research Communications,2009,384:357-361.
[41]Hampel H, Haslinger A, Scheloske M, et al. Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer's disease brain[J]. Eur Arch Psychiatry Clin Neurosci,2005,255(4):269-278.
[42]Braida D, Sacerdote P, Panerai AE, et al. Cognitive function in young and adult IL(interleukin)-6 deficient mice[J]. Behavioural Brain Research,2004,153:423-429.
[43]耿慧,钟远.衰老过程中小胶质细胞分泌白介素-6水平的改变[J].实用老年医学,2009,23(3)：1 97-199.
[44]刘小琦,刘祥琴,张本.血浆C反应蛋白在老年性及血管性痴呆患者中的变化的比较[J].现代预防医学,2009,36(2)：324-325.
[45]Dik MG, Jonker C, Hack CE, et al. Serum inflammatory proteins and cognitive decline in older persons[J]. Neurology,2005,64(8):1371-1377.
[46]van Oijen M, Witteman JC, Hofman A, et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia[J]. Stroke,2005,36(12):2637-2641.
[47]Nilsson K, Gustafson L, Hultberg B. C-reactive protein:vascular risk marker in elderly patients with mental illness[J]. Dement Geriatr Cogn Disord,2008,26(3):251-256.
[48]Lin HB, Yang XM, Li TJ, et al. Memory deficits and neurochemical changes induced by C-reactive protein in rats:implication in Alzheimer's disease[J]. Psychopharmacology,2009, 204(4):705-714.
[49]刘俊恒,潘继承,朱建一,等.阿尔茨海默病及血管性痴呆患者血脂、CRP、高半胱氨酸等指标的比较[J].临床检验杂志,2006,24(4)：311-312.
[50]Zaciragic A, Lepara O, Valjevac A, et al. Elevated serum C-reactive protein concentration in Bosnian patients with probable Alzheimer's disease[J]. J Alzheimer's Dis,2007,12(2): 151-156.
[51]Kravitz BA, Corrada MM, Kawas CH. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old[J]. Alzheimer's Dement,2009,5:318-323.
[52]O'Bryant SE, Waring SC, Hobson V, et al. Decreased C-reactive protein levels in Alzheimer disease[J]. J Geriatr Psychiatry Neurol,2010,23(1):49-53.
[53]Locascio JJ, Fukumoto H, Yap L, et al. Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease[J]. Arch Neurol,2008,65(6):776-785.
[54]王豪,瞿正万.总抗氧化状态、高敏c反应蛋白联合血脂检测在早老性痴呆症诊断中的应用研究[J].检验医学,2006,21(5)：465-467.
[55]蔡红芳.老年痴呆患者血脂、高敏C-反应蛋白与脑脊液乳酸含量同时测定的临床意义[J].现代中西医结合杂志,2008,17(13)：2037-2038.
[56]Filipcik P, Cente M, Ferencik M, et al. The role of oxidative stress in the pathogenesis of Alzheimer's disease[J]. Bratisl Lek Listy,2006,107(9-10):384-394.
[57]Moreira PI, Santos MS, Oliveira CR, et al. Alzheimer Disease and the Role of Free Radicals in the Pathogenesis of the Disease[J]. CNS & Neurological Disorders-Drug Targets,2008, 7(1):3-10.
[58]Zhang DL, Chen YQ, Jiang X, et al. Oxidative damage increased in presenilinl/presenilin2 conditional double knockout mice[J]. Neurosci Bull,2009,25(3):131-137.
[59]Goldsbury C, Whiteman IT, Jeong EV, et al. Oxidative stress increases levels of endogenous amyloid-beta peptides secreted from primary chick brain neurons [J]. Aging Cell,2008,7: 771-775.
[60]Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease[J]. Experimental Neurology,2009,218:286-292.
[61]Lustbader JW, Cirlli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease[J]. Science,2004,304:448-452.
[62]Sultana R, Boyd-Kimball D, Poon HF, et al. Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An approach to understand pathological and biochemical alterations in AD[J]. Neurobiol Aging,2006,27(11):1564-1576.
[63]陈祥,钟翎.阿尔茨海默病中p淀粉样蛋白神经毒性作用研究进展[J].中国神经精神疾病杂志,2008,34(5)：315-317.
[64]Hamel E, Nicolakakis N, Aboulkassim T, et al. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease[J]. Exp Physiol,2008,93(1):116-120.
[65]Guglielmotto M, Aragno M, Autelli R, et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury:role of oxidative stress and HIFlalpha[J]. J Neurochem,2009, 108(4):1045-1056.
[66]Malinski T. Nitric Oxide and Nitroxidative Stress in Alzheimer's Disease[J]. J Alzheimer's Dis,2007, 11(2):207-218.
[67]Colton CA, Wilcock DM, Wink DA, et al. The Effects of NOS2 Gene Deletion on Mice Expressing Mutated Human AβPP[J]. Journal of Alzheimer's Disease,2008,15:571-587.
[68]Boll MC, Alcaraz-Zubeldia M, Montes S, et al. Free Copper, Ferroxidase and SOD1 Activities, Lipid Peroxidation and NOx Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases[J]. Neurochem Res,2008,33(9):1717-1723.
[69]Martin-Aragon S, Bermejo-Bescos P, Benedi J, et al. Metalloproteinase's Activity and Oxidative Stress in Mild Cognitive Impairment and Alzheimer's Disease[J]. Neurochem Res, 2009,34:373-378.
[70]Massaad CA, Washington TM, Pautler RG, et al. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease[J]. PNAS,2009,106(32):13576-13581.
[71]李梅,林来祥,徐淑梅.H102对APP转基因小鼠胆碱能系统及自由基的影响[J].中国新药与临床杂志,2009,28(2)：106-109.
[72]徐青,孙强三,王晓红,等.升黄益智方对痴呆模型小鼠脑组织SOD活性的影响[J].中国老年学杂志,2007,27(8)：734-735.
[73]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[74]黄忠仕,林兴,李江,等.龙眼参多糖对D-半乳糖所致的痴呆小鼠脑组织NO、SOD、MDA的影响[J].中国老年学杂志,2005,25(2)：176-177.
[75]Flynn BL, Theesen KA. Pharmacologic management of Alzheimer disease part Ⅲ: nonsteroidal antiinflammatory drugs-emerging protective evidence? [J]. Ann Pharmacother, 1999,33(7-8):840-849.
[76]Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease:systematic review and meta-analysis of observational studies[J]. BMJ, 2003,327(7407):128.
[77]Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease:old and new mechanisms of action[J]. Journal of Neurochemistry,2004, 91:521-536.
[78]Kukar T, Golde TE. Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage[J]. Curr Top Med Chem,2008,8(1):47-53.
[79]林煜,贺顺龙,陈俊抛,等.吲哚美辛对p-淀粉样蛋白诱导脑内炎症损伤的保护作用[J].中华老年医学杂志,2002,21(2)：123-126.
[80]Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Acute treatment with the PPAR gamma agonist pioglitazone and ibuprofen reduces glial inflammation and A beta 1-42 levels in APPV717I transgenic mice[J]. Brain,2005,128:1442-1153.
[81]Geerts H. Drug evaluation:(R)-flurbi-profen--an enantiomer of flurbiprofen for the treatment of Alzheimer's disease[J]. Drugs,2007,10(2):121-133.
[82]Landreth G. PPARy agonists as new therapeutic agents for the treatment of Alzheimer's disease[J]. Experimental Neurology,2006,199:245-248.
[83]Luis Escribano, Ana-Maria Simon, Alberto Perez-Mediavia, Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model[J]. Biochemical and Biophysical Research Communications,2009,379:406-410.
[84]Nicolakakis N, Aboulkassim T, Ongali B, et al. Complete Rescue of Cerebrovascular Function in Aged Alzheimer's Disease Transgenic Mice by Antioxidants and Pioglitazone, a Peroxisome Proliferator-Activated Receptor y Agonist[J]. J Neurosci,2008,28(37):9287-9296.
[85]Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease[J]. Pharmacogenomics J,2006,6(4): 246-254.
[86]Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone:a preliminary study[J]. Am J Geriatr Psychiatry,2005,13(11):950-958.
[87]Seabrook T, Jiang LY, Maier M, et al. Minocycline Affects Microglia Activation, Aβ Deposition, and Behavior in APP-tg Mice[J]. GLIA,2006,53(7):776-782.
[88]Yan JJ, Cho JY, Kim HS, et al. Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid[J]. Br J Pharmacol,2001,133(1):89-96.
[89]Zhao L, He M, Jin WB, et al. Vitamin E administration improves learning and memory deficits in modeling Alzheimer's disease[J]. Chin J Clin Pharmacol Ther,2009,14(1):25-31.
[90]Olcese JM, Cao CH, Mori T, et al. Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease[J]. J Pineal Res,2009,47:82-96.
[91]王敏,张峰,李晓红,等.褪黑素对Alzheimer病模型大鼠认知功能和海马tau蛋白过度磷酸化的影响[J].临床神经病学杂志,2007,5：374-376.
[92]李楠,王建平.褪黑素对阿茨海默病大鼠海马突触素表达的影响[J].中国实用神经疾病杂志,2009,12(4)：16-18.
[93]Rockenstein E, Torrance M, Mante M, et al. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease[J]. J Neurosci Res,2006,83(7):1252-1261.
[94]Bolognesi ML, Matera R, Minatini A, et al. Alzheimer's disease:new approaches to drug discovery[J]. Curr Opin Chem Biol,2009,13:1-6.
[95]Ansari MA, Abdul HM, Joshi G, et al. Protective effect of quercetin in primary neurons against Abeta(1-42):relevance to Alzheimer's disease[J]. J Nutr Biochem,2009,20(4): 269-275.
[96]Sultana R, Newman SF, Abdul HM, et al. Protective effect of D609 against amyloid-beta 1-42-induced oxidative modification of neuronal proteins:redox proteomics study[J]. J Neurosci Res,2006,84(2):409-417.
[97]Dumont M, Wille E, Calingasan NY, et al. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease[J]. J Neurochem,2009,109(2):502-512.
[98]Moreira PI, Harris PL, Zhu X, et al. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts[J]. J Alzheimers Dis,2007,12(2):195-206.
[99]Wang HQ, Fan HH, Xu J, et al. Experimental basis for antioxidants TA99 series in the treatment of Alzheimer disease[J]. Chinese Journal of Clinical Rehabilitation,2005,9(13): 254-256.
[1]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11)：4-5.
[2]李浩,姚明江,赵文明,等.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1)：25-31.
[3]周明学,徐浩,陈可冀.中医脂毒、瘀毒与易损斑块关系的理论探讨[J].中国中医基础医学杂志,2007,13(10)：737-738.
[4]苏凤哲.毒邪论[J].中国中医基础医学杂志,2007,13(9)：649.
[5]肖苗苗.从肾论治阿尔茨海默病[J].河南中医,2008,28(1)：40-41.
[6]胡梅芳.老年性痴呆从肾虚痰瘀论治[J].临床研究论著,2009,33(3)：375-376.
[7]袁德培,邱幸凡,王平,等.肾虚髓衰、脑络痹阻是老年性痴呆的基本病机[J].中华中医药杂志,2008,23(8)：732-734.
[8]安红梅,胡兵,靳淼,等.顾明昌教授从虚论治神经精神系统疾病经验[J].中国中医急症,2006,15(10)：1119.
[9]安娜,郑卫莉,关继华.从中医气虚血瘀论治中老年轻度认知功能障碍[J].新疆中医药,2009,27(1)：6-7.
[10]于明秀.从阳明病变论述老年呆病的发病机制[J].新中医,2009,41(10)：1-2.
[11]王颖,纪立金.脾胃虚弱与老年性痴呆发病关系的探讨[J].福建中医药,2009,40(1)：59-60.
[12]隋华,刘晓亭,战丽彬.阴虚在老年期痴呆中的作用[J].中医药学刊,2005,23(6)：1090-1091.
[13]贾孟辉,贺晓慧,田建英.从阳虚论治老年痴呆症[J].新中医,2005,37(11)：80-81.
[14]王永炎.关于提高脑血管疾病疗效难点的思考[J].中国中西医结合杂志,1997,17(4)：195-196.
[15]郑春叶,卢明,黄燕.中风从毒论治浅议[J].中国中医药信息,2007,14(8)：5-6.
[16]宋建民,樊平.浅谈痰瘀致毒与中风的关系[J].陕西中医,2008,29(12)：1644.
[17]张敬华.中风发病启动之因——痰瘀毒邪[J].辽宁中医药大学学报,2008,10(1)：52-53.
[18]邹忆怀.中风病发病阶段“毒损脑络”临床特征的初步分析[J].北京中医药大学学报,2008,31(8)：509-511.
[19]张允岭,郭蓉娟,常富业,等.论中医毒邪的特性[J].北京中医药大学学报,2007,30(12)：800-801.
[20]常富业,张允岭,王永炎,等.《内经》毒论诠析[J].中国中医基础医学杂志,2007,13(12)：890-891.
[21]娄静.试论“毒邪”的概念[J].光明中医,2008,23(1)：18-20.
[22]吕崇山,李学军,杨叔禹.代谢综合征与痰瘀毒[J].亚太传统医药,2008,4(2)：21-22.
[23]邢颖,张兰,李林.参乌胶囊对APP转基因小鼠学习记忆能力及脑β-淀粉样肽含量的影响[J].中国康复理论与实践,2005,11(5)：324-326.
[24]邢颖,张兰,李林.参乌胶囊抑制阿尔茨海默病模型小鼠脑内β-淀粉样肽生成的机制研究[J].中国老年学杂志,2006,26(7)：924-925.
[25]张忠,薛卫国,白丽敏,等.益智汤对APP695转基因小鼠行为学及脑内β淀粉样蛋白及其前体蛋白的影响[J].北京中医药大学学报,2009,32(8)：553-556.
[26]缪丽莉,周爱玲,朱燕,等.脑益康对阿尔茨海默病模型大鼠脑组织内β淀粉样蛋白及其产生通路的影响[J].时珍国医国药,2009,20(3)：581-583.
[27]何明大,罗红波,张四方.脑灵汤对AD模型大鼠行为学及海马内APP mRNA表达的影响[J].中南大学学报(医学版),2006,31(1)：60-62.
[28]李黎,郑佳新.补阳还五汤对AD大鼠海马中IL-6、TNF-α的调节作用以及对Aβ1-40、β-APP蛋白表达的影响[J].中华中医药杂志,2008,23(11)：1038-1039.
[29]韩玉生,周忠光.补阳还五汤对Ap1-40所致老年性痴呆大鼠海马区p淀粉样前体蛋白及相关基因表达的影响[J].时珍国医国药,2009,20(1)：9-11.
[30]周志昆,曾红兵.黄芪三仙汤对Alzheimer模型大鼠脑海马区免疫炎性反应的影响[J].中药药理与临床,2006,22(2)：48-49.
[31]周志昆,曾红兵,黄兆胜,等.补肾活血方对阿尔茨海默病模型大鼠脑内胶质细胞的影响[J].中国中医基础医学杂志,2005,11(6)：425-427.
[32]张静,史宏,刘美莲,等.茵陈五苓散对阿尔茨海默病模型小鼠学习记忆及脑组织抗氧化能力的影响[J].贵阳中医学院学报,2009,31(2)：31-33.
[33]张利莉,覃强,黄好德,等.中药对拟阿尔茨海默病动物模型小鼠治疗后大脑、肝等组织生化指标的变化[J].中国实用医药,2008,3(5)：14-17.
[34]蔡秋芳.调心方治疗老年性痴呆机理研究[J].吉林中医药,2008,28(3)：211-212.
[35]张沁园.益气聪明汤防治痴呆小鼠作用机制实验研究[J].中国中医药信息杂志,2008,15(增刊)：25-26.
[36]刘春玲,孙晓冬,胡静,等.补阳还五汤与地黄饮子对拟AD大鼠行为学、MAO和LIP影响 [J].中医药信息,2009,26(2)：55-56.
[37]朱燕,周爱玲,茅家慧.脑益康对阿尔茨海默病模型小鼠学习记忆的影响[J].中国临床药理学与治疗学,2005,10(1)：79-82.
[38]周静,周爱玲,路燕.脑益康对阿尔茨海默病大鼠tau蛋白过度磷酸化及其相关酶类表达的影响[J].苏州大学学报(医学版),2009,29(3)：426-429.
[39]李浩,刘剑刚,姚明江,等.还脑益聪方对老龄认知障碍大鼠脂质代谢和海马内质网Ap相关结合蛋白表达的影响[J].中国中医基础医学杂志,2009,15(5)：354-357.
[40]姚明江,刘剑刚,李浩,等.还脑益聪方对早期认知功能障碍大鼠血浆P-选择素、血浆纤溶酶原激活物抑制剂和血液流变学指标的影响[J].中国微循环,2009,13(4)：254-258.
[41]李浩,姚明江,徐立,等.还脑益聪方对认知功能障碍大鼠认知功能及海马Bcl-2,Bax蛋白表达的影响[J].中国中药杂志,2009,34(20)：2622-2625.
[42]吴之煌,张晓霞,寇焰.补肾填髓汤治疗老年性脑痴呆30例临床观察[J].北京中医药,2008,27(9)：715-716.
[43]唐百冬,何军锋.自拟补肾涤痰祛瘀汤治疗老年性痴呆30例临床观察[J].中医药导报,2008,14(12)：26-27.
[44]陈岩,袁勇.活脑方治疗阿尔茨海默病肾虚髓减证临床研究[J].山东医药,2008,48(32)：81-82.
[45]唐丽颖.自拟健智汤治疗老年性痴呆疗效观察[J].浙江中西医结合杂志,2009,19(10)：614-615.
[46]吴向东,薛艳萍.保元益智散治疗老年痴呆52例临床观察[J].中国中医药科技,2008,15(4)：252.
[47]寇胜玲,赵姗.补肾化痰通络治疗老年性痴呆48例[J].河北中医药学报,2008,23(4)：11.
[48]季铁铮.地黄饮子加减合七宝美髯丹治疗老年痴呆症40例疗效观察[J].新中医,2006,38(4)：50-51.
[49]庄海新,于兆安.乐脉颗粒治疗老年期痴呆临床观察及对临床电生理影响[J].吉林中医药,2008,28(4)：264-265.
[50]李建美,陈凤兰,李桂玲.开窍醒脑通络法治疗老年痴呆症25例[J].新中医,2006,38(6)：71-72.
[51]张德英,韩红伟,谷银强.繁木泻土法治疗老年性痴呆60例[J].陕西中医,2008,29(6)：706-707.
[52]李桂英,唐功香,李永华.半夏白术天麻汤治疗阿尔茨海默病[J].临床和实验医学杂志,2006,5(5)：602.
[53]任鹏鸣,余紫燕.清痰汤治疗老年性痴呆60例[J].山东中医杂志,2008,27(5)：302-303.
[54]马玉斌,孙立新.黄芪益脑宁治疗老年痴呆症的临床研究[J].数理医药学杂志,2008,21(4)：429-430.
[55]张秀云,李振民.开窍益智方治疗阿尔茨海默病120例[J].陕西中医,2008,29(10)：1311-1312.
[56]安丽芝,张秀云,董会文,等.清心开窍法对阿尔茨海默病患者脑电图的影响[J].四川中医,2008,26(6)：66-67.
[57]王慧玲,董克礼.益智健脑颗粒对阿尔茨海默病患者脑内促炎症细胞因子的影响[J].湖南中医药大学学报,2008,28(2)：54-56.
[58]孙彩虹,张淑华,刘召茹治阿汤治疗阿尔茨海默病的临床研究[J].哈尔滨医药,2008,28(5)：41-42.
[59]董桂英,赵世珂,郭立华,等.清脑颐智灵治疗阿尔茨海默病60例临床观察[J].中西医结合心脑血管病杂志,2003,1(4)：236.
[1]盛树力.老年性痴呆及相关疾病[M].北京：科学技术文献出版社,2006.43-44.
[2]盛树力.老年性痴呆发病机理研究进展和药物治疗未来战略[J].中国医学科学院学报,2004,26(2)：101-103.
[3]郑隽,王永红.阿尔茨海默病治疗的研究进展[J].重庆医科大学学报,2007,32(增刊)：30-32.
[4]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”与轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11)：4-5.
[5]李浩,姚明江,赵文明,等.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1)：25-30.
[6]李浩,刘剑刚,姚明江,等.还脑益聪方对老龄认知障碍大鼠脂质代谢和海马内质网Ap相关结合蛋白表达的影响[J].中国中医基础医学杂志,2009,15(5)：354-357.
[7]姚明江,刘剑刚,李浩,等.还脑益聪方对早期认知功能障碍大鼠血浆P-选择素、血浆纤溶酶原激活物抑制剂和血液流变学指标的影响[J].中国微循环,2009,13(4)：254-258.
[8]李浩,姚明江,徐立,等.还脑益聪方对认知功能障碍大鼠认知功能及海马Bc1-2,Bax蛋白表达的影响[J].中国中药杂志,2009,34(20)：2622-2625.
[9]Zhang YW, Xu H. Molecular and cellular mechanisms for Alzheimer's disease:understanding APP metabolism[J]. Curr Mol Med,2007,7(7):687-696.
[10]马永兴,俞卓伟.现代痴呆学[M].北京：科学技术文献出版社,2008,274.
[11]Dewachter I, vanDorpe J, Spittaels K, et al. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin 1 on amyloid biochemistry and pathology APP/London mice[J]. Exp Gerontol,2000,35(627):831-841.
[12]秦川,朱华,常洋,等.阿尔茨海默症转基因小鼠的初步行为学评价[J].上海实验动物科学,2000,20(4)：210-211.
[13]黄澜,朱华,高虹,等.不同月龄人App老年痴呆病转基因小鼠行为学观察比较[J].中国老年性杂志,2004,24(12)：1185-1186.
[14]秦川,朱华,张兵林,等.阿尔茨海默病转基因动物模型脑组织病理学及免疫组化研究[J].中国实验动物学报,2000,8：213-217.
[15]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[16]White AM, Mattews DB, Best PJ. Ethanol, memory, and hippocampal function:a review of recent findings[J]. Hippocampus,2002,10(1):88-93.
[17]邢颖,张兰,李林.参乌胶囊抑制阿尔茨海默病模型小鼠脑内p-淀粉样肽生成的机制研究[J].中国老年学杂志,2006,26(7)：924-925.
[18]徐意.金思维提取物对AD模型鼠脑内p淀粉样肽及神经可塑性的影响[D]北京中医药大学,2006.
[19]邢颖,张兰,李林.参乌胶囊对APP转基因小鼠学习记忆能力及脑p-淀粉样肽含量的影响[J]中国康复理论与实践,2005,11(5)：324-326.
[20]Granic I, Dolga AM, Nijholt IM, et al. Inflammation and NF-κB in Alzheimer's Disease and Diabetes[J]. Journal of Alzheimer's Disease,2009,16:809-821.
[21]Paris D, Patel N, Quadros A, et al. Inhibition of Abeta production by NF-kappaB inhibitors[J]. Neurosci Lett,2007,415(1):11-16.
[22]Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in beta-amyloid-treated C6 glioma cells[J].Int J Mol Med,2006, 17(6):1069-1075.
[23]Jiang QG, Heneka M, Landreth GE. The Role of Peroxisome Proliferator-Activated Receptor-γ (PPARy) in Alzheimer's Disease[J]. CNS Drugs,2008,22(1):1-14.
[24]王英杰.旋覆花素对阿尔茨海默病的干预及其机制的实验研究[D].河北医科大学,2008.
[25]Moreira PI, Santos MS, Oliveira CR, et al. Alzheimer Disease and the Role of Free Radicals in the Pathogenesis of the Disease[J]. CNS & Neurological Disorders-Drug Targets,2008, 7(1):3-10.
[26]徐青,孙强三,王晓红,等.升黄益智方对痴呆模型小鼠脑组织SOD活性的影响[J].中国老年学杂志,2007,27(8)：734-735.
[27]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[28]李梅,林来祥,徐淑梅.H102对APP转基因小鼠胆碱能系统及自由基的影响[J].中国新药与临床杂志,2009,28(2)：106-109.
[29]Hamel E, Nicolakakis N, Aboulkassim T, et al. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease[J]. Exp Physiol,2008,93(1):116-120.
[30]邢颖,张兰,李林.二苯乙烯苷对APP转基因小鼠学习记忆能力和脑内β淀粉样肽表达的影响[J].中国新药杂志,2006,15(7)：510-513.
[31]杨小燕.制何首乌多糖对痴呆模型小鼠学习记忆能力及脑内酶活性的影响[J].药学进展,2005,29(12)：557-559.
[32]余上才,李晓玉.人参皂甙及β淀粉样蛋白对大鼠神经胶质瘤C6细胞产生前炎性细胞因子的影响[J].中国药理学会通讯,2000,17(4)：18.
[33]李玮,李林,褚燕琦,等.人参皂甙对β淀粉样蛋白诱导THP-1单核细胞-氧化氮合酶和-氧化氮的影响[J].中国神经免疫学和神经病学杂志,2006,13(2)：94-96.
[34]厉曙光,白莉华,王力强,等.人参对果蝇寿命的影响及其抗氧化作用[J].卫生研究,2008,37(1)：104-105.
[35]李彩虹,周克元.黄连活性成分的作用及机制研究进展[J].时珍国医国药,2010,21(2)：466-468.
[36]方青,詹小萍,莫剑翎,等.黄连解毒汤对AD大鼠的治疗作用及对细胞因子含量的影响[J].中国中药杂志,2004,29(6)：575-577.
[37]乔丽,林娜.黄连抗氧化作用的研究进展[C].第三届国际传统医药大会文集,2004：273.
[2]Kang J, Lemaire HG, Unterbeck A, et al.The precursor of Alzheimer's disease amyloidA4 protein resembles a cell-surface receptor[J]. Nature,1987,325(6106):733-736.
[3]刘元,华茜,雷洪涛,等.老年斑p淀粉样蛋白的清除机制[J].现代生物医学进展,2008,8(1)：152-154.
[4]Hooper C, Fry VA, Sevastou IG, et al. Scavenger receptor control of chromogranin A-induced microglial stress and neurotoxic cascades[J]. FEBS Lett,2009,583(21):3461-3466.
[5]Shepherd C, McCann H, Halliday GM. Variations in the neuropathology of familial Alzheimer's disease[J]. Acta Neuropathol,2009,118(1):37-52.
[6]Li M, Chen LY, Lee D, et al. The role of intracellular amyloid beta in Alzheimer's disease[J]. Prog Neurobiol,2007,83:131-139.
[7]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[8]Pimplikar SW. Reassessing the amyloid cascade hypothesis of Alzheimer's disease[J]. Int J Biochem Cell Biol,2009,41:1261-1268.
[9]Sotthibundhu A, Sykes AM, Fox B, et al. Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor[J]. J Neurosci,2008,28(15):3941-3946.
[10]Dong Y, Zhang G, Zhang B, et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels[J]. Arch Neurol,2009,66(5):620-631.
[11]Frasca G, Carbonaro V, Merlo S, et al. Integrins mediate beta-amyloid-induced cell-cycle activation and neuronal death[J]. J Neurosci Res,2008,86(2):350-355.
[12]谢朝阳,祝其锋,吴斌华.Ap25-35对PC12细胞周期及P21、CDK4、E2F1、BAX基因表达的影响[J].基础医学与临床,2009,29(4)：383-387.
[13]Cao X, Wei Z, Gabriel GG, et al. Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures:implications for
Alzheimer disease-related pathology[J]. BMC Neuroscience,2007,8(1):73.
[14]Puzzo D, Vitolo O, Trinchese F, et al. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity[J]. J Neurosci,2005,25(29):6887-6897.
[15]Lee JW, Lee YK, Yuk DY, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation[J]. J Neuroinflamm, 2008,29(5):37.
[16]蔡志友.小胶质细胞与阿尔茨海默病神经炎症[J].重庆医学,2008,37(7)：735-737.
[17]蔡志友.星形胶质细胞与阿尔茨海默病[J].重庆医学,2009,38(6)：733-735.
[18]杨小慧,姜招峰.小胶质细胞在阿尔茨海默病中的作用[J].生命的化学,2008,28(4)：431-433.
[19]Block ML, Hong JS. Chronic microglial activation and progressive dopaminergic neurotoxicity[J]. Biochem Soc Trans,2007,35(5):1127-1132.
[20]潘晓东,陈晓春,朱元贵,等.寡聚态β-淀粉样肽1-42可通过胶质-炎症反应损伤神经元[J].解剖学报,2008,39(6)：804-809.
[21]Walter S, Letiembre M, Liu Y, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease[J]. Cell Physiol Biochem,2007,20(6):947-956.
[22]Jin JJ, Kim HD, Maxwell JA, et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease[J]. J Neuroinflammation,2008,5:23-33.
[23]Farfara D, Lifshitz V, Frenkel D. Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease[J]. Cell Mol Med,2008,12(3):762-780.
[24]Sokolova A, Hill MD, Rahimi F, et al. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease[J]. Brain Pathol,2009, 19(3):392-398.
[25]Zhou J, Fonseca MI, Pisalyaput K, et al. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease[J]. J Neurochem,2008,106(5):2080.
[26]Granic I, Dolga AM, Nijholt IM, et al. Inflammation and NF-κB in Alzheimer's Disease and Diabetes[J]. Journal of Alzheimer's Disease,2009,16:809-821.
[27]Paris D, Patel N, Quadros A, et al. Inhibition of Abeta production by NF-kappaB inhibitors[J]. Neurosci Lett,2007,415(1):11-16.
[28]Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in beta-amyloid-treated C6 glioma cells[J]. Int J Mol Med, 2006,17(6):1069-1075.
[29]龚云涛,王晓民NF-κB与中枢神经系统退变性疾病[J].生命科学,2004,16(5)：280-283.
[30]冯梅,王奇,陈云波.核因子κB与胶质细胞在阿尔茨海默病中的研究进展[J].中国老年学杂志,2005,25(4)：484.
[31]Yang Y, Zhang EM, Zheng XX. Inducible nitric oxide synthase and NFκB signaling in amyloid (3-peptide induced neuron death and apoptosis[J]. Chin J Neuromed,2005,4(3): 295-299.
[32]Choi S, Kim JH, Roh EJ, et al. Nuclear factor-kappaB activated by capacitative Ca2+entry enhances muscarinic receptor-mediated soluble amyloid precursor protein (sAPPalpha) release in SH-SY5Y cells[J]. J Biol Chem,2006,281 (18):12722-12728.
[33]Heneka MT, Landreth GE. PPARs in the brain[J]. Biochimica et Biophysica Acta,2007,1771: 1031-1045.
[34]Bookout AL, Jeong Y, Downes M, et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network[J]. Cell 2006,126 (4):789-799.
[35]Victor NA, Wanderi EW, Gamboa J, et al. Altered PPARy expression and activation after transient focal ischemia in rats[J]. Eur J Neurosci 2006,24(6):1653-1663.
[36]de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease[J]. J Alzheimer's Dis,2006,9(2):167-181.
[37]Jiang QG, Heneka M, Landreth GE. The Role of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) in Alzheimer's Disease[J]. CNS Drugs,2008,22(1):1-14.
[38]Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPAR gamma[J]. Proc Natl Acad Sci USA,2006,103(2):443-448.
[39]Cristina D'ABRAMO, Sara MASSONE, Jean-Marc ZINGG, et al. Role of peroxisome proliferator-activated receptory in amyloid precursor protein processing and amyloid (3-mediated cell death[J]. Biochem,2005,391:693-698.
[40]Du J, Sun B, Chen K, et al. Antagonist of peroxisome proliferator-activated receptor y induces cerebellar amyloid-β levels and motor dysfunction in APP/PS1 transgenic mice[J].
Biochemical and Biophysical Research Communications,2009,384:357-361.
[41]Hampel H, Haslinger A, Scheloske M, et al. Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer's disease brain[J]. Eur Arch Psychiatry Clin Neurosci,2005,255(4):269-278.
[42]Braida D, Sacerdote P, Panerai AE, et al. Cognitive function in young and adult IL(interleukin)-6 deficient mice[J]. Behavioural Brain Research,2004,153:423-429.
[43]耿慧,钟远.衰老过程中小胶质细胞分泌白介素-6水平的改变[J].实用老年医学,2009,23(3)：1 97-199.
[44]刘小琦,刘祥琴,张本.血浆C反应蛋白在老年性及血管性痴呆患者中的变化的比较[J].现代预防医学,2009,36(2)：324-325.
[45]Dik MG, Jonker C, Hack CE, et al. Serum inflammatory proteins and cognitive decline in older persons[J]. Neurology,2005,64(8):1371-1377.
[46]van Oijen M, Witteman JC, Hofman A, et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia[J]. Stroke,2005,36(12):2637-2641.
[47]Nilsson K, Gustafson L, Hultberg B. C-reactive protein:vascular risk marker in elderly patients with mental illness[J]. Dement Geriatr Cogn Disord,2008,26(3):251-256.
[48]Lin HB, Yang XM, Li TJ, et al. Memory deficits and neurochemical changes induced by C-reactive protein in rats:implication in Alzheimer's disease[J]. Psychopharmacology,2009, 204(4):705-714.
[49]刘俊恒,潘继承,朱建一,等.阿尔茨海默病及血管性痴呆患者血脂、CRP、高半胱氨酸等指标的比较[J].临床检验杂志,2006,24(4)：311-312.
[50]Zaciragic A, Lepara O, Valjevac A, et al. Elevated serum C-reactive protein concentration in Bosnian patients with probable Alzheimer's disease[J]. J Alzheimer's Dis,2007,12(2): 151-156.
[51]Kravitz BA, Corrada MM, Kawas CH. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old[J]. Alzheimer's Dement,2009,5:318-323.
[52]O'Bryant SE, Waring SC, Hobson V, et al. Decreased C-reactive protein levels in Alzheimer disease[J]. J Geriatr Psychiatry Neurol,2010,23(1):49-53.
[53]Locascio JJ, Fukumoto H, Yap L, et al. Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease[J]. Arch Neurol,2008,65(6):776-785.
[54]王豪,瞿正万.总抗氧化状态、高敏c反应蛋白联合血脂检测在早老性痴呆症诊断中的应用研究[J].检验医学,2006,21(5)：465-467.
[55]蔡红芳.老年痴呆患者血脂、高敏C-反应蛋白与脑脊液乳酸含量同时测定的临床意义[J].现代中西医结合杂志,2008,17(13)：2037-2038.
[56]Filipcik P, Cente M, Ferencik M, et al. The role of oxidative stress in the pathogenesis of Alzheimer's disease[J]. Bratisl Lek Listy,2006,107(9-10):384-394.
[57]Moreira PI, Santos MS, Oliveira CR, et al. Alzheimer Disease and the Role of Free Radicals in the Pathogenesis of the Disease[J]. CNS & Neurological Disorders-Drug Targets,2008, 7(1):3-10.
[58]Zhang DL, Chen YQ, Jiang X, et al. Oxidative damage increased in presenilinl/presenilin2 conditional double knockout mice[J]. Neurosci Bull,2009,25(3):131-137.
[59]Goldsbury C, Whiteman IT, Jeong EV, et al. Oxidative stress increases levels of endogenous amyloid-beta peptides secreted from primary chick brain neurons [J]. Aging Cell,2008,7: 771-775.
[60]Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease[J]. Experimental Neurology,2009,218:286-292.
[61]Lustbader JW, Cirlli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease[J]. Science,2004,304:448-452.
[62]Sultana R, Boyd-Kimball D, Poon HF, et al. Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An approach to understand pathological and biochemical alterations in AD[J]. Neurobiol Aging,2006,27(11):1564-1576.
[63]陈祥,钟翎.阿尔茨海默病中p淀粉样蛋白神经毒性作用研究进展[J].中国神经精神疾病杂志,2008,34(5)：315-317.
[64]Hamel E, Nicolakakis N, Aboulkassim T, et al. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease[J]. Exp Physiol,2008,93(1):116-120.
[65]Guglielmotto M, Aragno M, Autelli R, et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury:role of oxidative stress and HIFlalpha[J]. J Neurochem,2009, 108(4):1045-1056.
[66]Malinski T. Nitric Oxide and Nitroxidative Stress in Alzheimer's Disease[J]. J Alzheimer's Dis,2007, 11(2):207-218.
[67]Colton CA, Wilcock DM, Wink DA, et al. The Effects of NOS2 Gene Deletion on Mice Expressing Mutated Human AβPP[J]. Journal of Alzheimer's Disease,2008,15:571-587.
[68]Boll MC, Alcaraz-Zubeldia M, Montes S, et al. Free Copper, Ferroxidase and SOD1 Activities, Lipid Peroxidation and NOx Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases[J]. Neurochem Res,2008,33(9):1717-1723.
[69]Martin-Aragon S, Bermejo-Bescos P, Benedi J, et al. Metalloproteinase's Activity and Oxidative Stress in Mild Cognitive Impairment and Alzheimer's Disease[J]. Neurochem Res, 2009,34:373-378.
[70]Massaad CA, Washington TM, Pautler RG, et al. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease[J]. PNAS,2009,106(32):13576-13581.
[71]李梅,林来祥,徐淑梅.H102对APP转基因小鼠胆碱能系统及自由基的影响[J].中国新药与临床杂志,2009,28(2)：106-109.
[72]徐青,孙强三,王晓红,等.升黄益智方对痴呆模型小鼠脑组织SOD活性的影响[J].中国老年学杂志,2007,27(8)：734-735.
[73]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[74]黄忠仕,林兴,李江,等.龙眼参多糖对D-半乳糖所致的痴呆小鼠脑组织NO、SOD、MDA的影响[J].中国老年学杂志,2005,25(2)：176-177.
[75]Flynn BL, Theesen KA. Pharmacologic management of Alzheimer disease part Ⅲ: nonsteroidal antiinflammatory drugs-emerging protective evidence? [J]. Ann Pharmacother, 1999,33(7-8):840-849.
[76]Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease:systematic review and meta-analysis of observational studies[J]. BMJ, 2003,327(7407):128.
[77]Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease:old and new mechanisms of action[J]. Journal of Neurochemistry,2004, 91:521-536.
[78]Kukar T, Golde TE. Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage[J]. Curr Top Med Chem,2008,8(1):47-53.
[79]林煜,贺顺龙,陈俊抛,等.吲哚美辛对p-淀粉样蛋白诱导脑内炎症损伤的保护作用[J].中华老年医学杂志,2002,21(2)：123-126.
[80]Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Acute treatment with the PPAR gamma agonist pioglitazone and ibuprofen reduces glial inflammation and A beta 1-42 levels in APPV717I transgenic mice[J]. Brain,2005,128:1442-1153.
[81]Geerts H. Drug evaluation:(R)-flurbi-profen--an enantiomer of flurbiprofen for the treatment of Alzheimer's disease[J]. Drugs,2007,10(2):121-133.
[82]Landreth G. PPARy agonists as new therapeutic agents for the treatment of Alzheimer's disease[J]. Experimental Neurology,2006,199:245-248.
[83]Luis Escribano, Ana-Maria Simon, Alberto Perez-Mediavia, Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model[J]. Biochemical and Biophysical Research Communications,2009,379:406-410.
[84]Nicolakakis N, Aboulkassim T, Ongali B, et al. Complete Rescue of Cerebrovascular Function in Aged Alzheimer's Disease Transgenic Mice by Antioxidants and Pioglitazone, a Peroxisome Proliferator-Activated Receptor y Agonist[J]. J Neurosci,2008,28(37):9287-9296.
[85]Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease[J]. Pharmacogenomics J,2006,6(4): 246-254.
[86]Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone:a preliminary study[J]. Am J Geriatr Psychiatry,2005,13(11):950-958.
[87]Seabrook T, Jiang LY, Maier M, et al. Minocycline Affects Microglia Activation, Aβ Deposition, and Behavior in APP-tg Mice[J]. GLIA,2006,53(7):776-782.
[88]Yan JJ, Cho JY, Kim HS, et al. Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid[J]. Br J Pharmacol,2001,133(1):89-96.
[89]Zhao L, He M, Jin WB, et al. Vitamin E administration improves learning and memory deficits in modeling Alzheimer's disease[J]. Chin J Clin Pharmacol Ther,2009,14(1):25-31.
[90]Olcese JM, Cao CH, Mori T, et al. Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease[J]. J Pineal Res,2009,47:82-96.
[91]王敏,张峰,李晓红,等.褪黑素对Alzheimer病模型大鼠认知功能和海马tau蛋白过度磷酸化的影响[J].临床神经病学杂志,2007,5：374-376.
[92]李楠,王建平.褪黑素对阿茨海默病大鼠海马突触素表达的影响[J].中国实用神经疾病杂志,2009,12(4)：16-18.
[93]Rockenstein E, Torrance M, Mante M, et al. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease[J]. J Neurosci Res,2006,83(7):1252-1261.
[94]Bolognesi ML, Matera R, Minatini A, et al. Alzheimer's disease:new approaches to drug discovery[J]. Curr Opin Chem Biol,2009,13:1-6.
[95]Ansari MA, Abdul HM, Joshi G, et al. Protective effect of quercetin in primary neurons against Abeta(1-42):relevance to Alzheimer's disease[J]. J Nutr Biochem,2009,20(4): 269-275.
[96]Sultana R, Newman SF, Abdul HM, et al. Protective effect of D609 against amyloid-beta 1-42-induced oxidative modification of neuronal proteins:redox proteomics study[J]. J Neurosci Res,2006,84(2):409-417.
[97]Dumont M, Wille E, Calingasan NY, et al. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease[J]. J Neurochem,2009,109(2):502-512.
[98]Moreira PI, Harris PL, Zhu X, et al. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts[J]. J Alzheimers Dis,2007,12(2):195-206.
[99]Wang HQ, Fan HH, Xu J, et al. Experimental basis for antioxidants TA99 series in the treatment of Alzheimer disease[J]. Chinese Journal of Clinical Rehabilitation,2005,9(13): 254-256.
[1]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11)：4-5.
[2]李浩,姚明江,赵文明,等.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1)：25-31.
[3]周明学,徐浩,陈可冀.中医脂毒、瘀毒与易损斑块关系的理论探讨[J].中国中医基础医学杂志,2007,13(10)：737-738.
[4]苏凤哲.毒邪论[J].中国中医基础医学杂志,2007,13(9)：649.
[5]肖苗苗.从肾论治阿尔茨海默病[J].河南中医,2008,28(1)：40-41.
[6]胡梅芳.老年性痴呆从肾虚痰瘀论治[J].临床研究论著,2009,33(3)：375-376.
[7]袁德培,邱幸凡,王平,等.肾虚髓衰、脑络痹阻是老年性痴呆的基本病机[J].中华中医药杂志,2008,23(8)：732-734.
[8]安红梅,胡兵,靳淼,等.顾明昌教授从虚论治神经精神系统疾病经验[J].中国中医急症,2006,15(10)：1119.
[9]安娜,郑卫莉,关继华.从中医气虚血瘀论治中老年轻度认知功能障碍[J].新疆中医药,2009,27(1)：6-7.
[10]于明秀.从阳明病变论述老年呆病的发病机制[J].新中医,2009,41(10)：1-2.
[11]王颖,纪立金.脾胃虚弱与老年性痴呆发病关系的探讨[J].福建中医药,2009,40(1)：59-60.
[12]隋华,刘晓亭,战丽彬.阴虚在老年期痴呆中的作用[J].中医药学刊,2005,23(6)：1090-1091.
[13]贾孟辉,贺晓慧,田建英.从阳虚论治老年痴呆症[J].新中医,2005,37(11)：80-81.
[14]王永炎.关于提高脑血管疾病疗效难点的思考[J].中国中西医结合杂志,1997,17(4)：195-196.
[15]郑春叶,卢明,黄燕.中风从毒论治浅议[J].中国中医药信息,2007,14(8)：5-6.
[16]宋建民,樊平.浅谈痰瘀致毒与中风的关系[J].陕西中医,2008,29(12)：1644.
[17]张敬华.中风发病启动之因——痰瘀毒邪[J].辽宁中医药大学学报,2008,10(1)：52-53.
[18]邹忆怀.中风病发病阶段“毒损脑络”临床特征的初步分析[J].北京中医药大学学报,2008,31(8)：509-511.
[19]张允岭,郭蓉娟,常富业,等.论中医毒邪的特性[J].北京中医药大学学报,2007,30(12)：800-801.
[20]常富业,张允岭,王永炎,等.《内经》毒论诠析[J].中国中医基础医学杂志,2007,13(12)：890-891.
[21]娄静.试论“毒邪”的概念[J].光明中医,2008,23(1)：18-20.
[22]吕崇山,李学军,杨叔禹.代谢综合征与痰瘀毒[J].亚太传统医药,2008,4(2)：21-22.
[23]邢颖,张兰,李林.参乌胶囊对APP转基因小鼠学习记忆能力及脑β-淀粉样肽含量的影响[J].中国康复理论与实践,2005,11(5)：324-326.
[24]邢颖,张兰,李林.参乌胶囊抑制阿尔茨海默病模型小鼠脑内β-淀粉样肽生成的机制研究[J].中国老年学杂志,2006,26(7)：924-925.
[25]张忠,薛卫国,白丽敏,等.益智汤对APP695转基因小鼠行为学及脑内β淀粉样蛋白及其前体蛋白的影响[J].北京中医药大学学报,2009,32(8)：553-556.
[26]缪丽莉,周爱玲,朱燕,等.脑益康对阿尔茨海默病模型大鼠脑组织内β淀粉样蛋白及其产生通路的影响[J].时珍国医国药,2009,20(3)：581-583.
[27]何明大,罗红波,张四方.脑灵汤对AD模型大鼠行为学及海马内APP mRNA表达的影响[J].中南大学学报(医学版),2006,31(1)：60-62.
[28]李黎,郑佳新.补阳还五汤对AD大鼠海马中IL-6、TNF-α的调节作用以及对Aβ1-40、β-APP蛋白表达的影响[J].中华中医药杂志,2008,23(11)：1038-1039.
[29]韩玉生,周忠光.补阳还五汤对Ap1-40所致老年性痴呆大鼠海马区p淀粉样前体蛋白及相关基因表达的影响[J].时珍国医国药,2009,20(1)：9-11.
[30]周志昆,曾红兵.黄芪三仙汤对Alzheimer模型大鼠脑海马区免疫炎性反应的影响[J].中药药理与临床,2006,22(2)：48-49.
[31]周志昆,曾红兵,黄兆胜,等.补肾活血方对阿尔茨海默病模型大鼠脑内胶质细胞的影响[J].中国中医基础医学杂志,2005,11(6)：425-427.
[32]张静,史宏,刘美莲,等.茵陈五苓散对阿尔茨海默病模型小鼠学习记忆及脑组织抗氧化能力的影响[J].贵阳中医学院学报,2009,31(2)：31-33.
[33]张利莉,覃强,黄好德,等.中药对拟阿尔茨海默病动物模型小鼠治疗后大脑、肝等组织生化指标的变化[J].中国实用医药,2008,3(5)：14-17.
[34]蔡秋芳.调心方治疗老年性痴呆机理研究[J].吉林中医药,2008,28(3)：211-212.
[35]张沁园.益气聪明汤防治痴呆小鼠作用机制实验研究[J].中国中医药信息杂志,2008,15(增刊)：25-26.
[36]刘春玲,孙晓冬,胡静,等.补阳还五汤与地黄饮子对拟AD大鼠行为学、MAO和LIP影响 [J].中医药信息,2009,26(2)：55-56.
[37]朱燕,周爱玲,茅家慧.脑益康对阿尔茨海默病模型小鼠学习记忆的影响[J].中国临床药理学与治疗学,2005,10(1)：79-82.
[38]周静,周爱玲,路燕.脑益康对阿尔茨海默病大鼠tau蛋白过度磷酸化及其相关酶类表达的影响[J].苏州大学学报(医学版),2009,29(3)：426-429.
[39]李浩,刘剑刚,姚明江,等.还脑益聪方对老龄认知障碍大鼠脂质代谢和海马内质网Ap相关结合蛋白表达的影响[J].中国中医基础医学杂志,2009,15(5)：354-357.
[40]姚明江,刘剑刚,李浩,等.还脑益聪方对早期认知功能障碍大鼠血浆P-选择素、血浆纤溶酶原激活物抑制剂和血液流变学指标的影响[J].中国微循环,2009,13(4)：254-258.
[41]李浩,姚明江,徐立,等.还脑益聪方对认知功能障碍大鼠认知功能及海马Bcl-2,Bax蛋白表达的影响[J].中国中药杂志,2009,34(20)：2622-2625.
[42]吴之煌,张晓霞,寇焰.补肾填髓汤治疗老年性脑痴呆30例临床观察[J].北京中医药,2008,27(9)：715-716.
[43]唐百冬,何军锋.自拟补肾涤痰祛瘀汤治疗老年性痴呆30例临床观察[J].中医药导报,2008,14(12)：26-27.
[44]陈岩,袁勇.活脑方治疗阿尔茨海默病肾虚髓减证临床研究[J].山东医药,2008,48(32)：81-82.
[45]唐丽颖.自拟健智汤治疗老年性痴呆疗效观察[J].浙江中西医结合杂志,2009,19(10)：614-615.
[46]吴向东,薛艳萍.保元益智散治疗老年痴呆52例临床观察[J].中国中医药科技,2008,15(4)：252.
[47]寇胜玲,赵姗.补肾化痰通络治疗老年性痴呆48例[J].河北中医药学报,2008,23(4)：11.
[48]季铁铮.地黄饮子加减合七宝美髯丹治疗老年痴呆症40例疗效观察[J].新中医,2006,38(4)：50-51.
[49]庄海新,于兆安.乐脉颗粒治疗老年期痴呆临床观察及对临床电生理影响[J].吉林中医药,2008,28(4)：264-265.
[50]李建美,陈凤兰,李桂玲.开窍醒脑通络法治疗老年痴呆症25例[J].新中医,2006,38(6)：71-72.
[51]张德英,韩红伟,谷银强.繁木泻土法治疗老年性痴呆60例[J].陕西中医,2008,29(6)：706-707.
[52]李桂英,唐功香,李永华.半夏白术天麻汤治疗阿尔茨海默病[J].临床和实验医学杂志,2006,5(5)：602.
[53]任鹏鸣,余紫燕.清痰汤治疗老年性痴呆60例[J].山东中医杂志,2008,27(5)：302-303.
[54]马玉斌,孙立新.黄芪益脑宁治疗老年痴呆症的临床研究[J].数理医药学杂志,2008,21(4)：429-430.
[55]张秀云,李振民.开窍益智方治疗阿尔茨海默病120例[J].陕西中医,2008,29(10)：1311-1312.
[56]安丽芝,张秀云,董会文,等.清心开窍法对阿尔茨海默病患者脑电图的影响[J].四川中医,2008,26(6)：66-67.
[57]王慧玲,董克礼.益智健脑颗粒对阿尔茨海默病患者脑内促炎症细胞因子的影响[J].湖南中医药大学学报,2008,28(2)：54-56.
[58]孙彩虹,张淑华,刘召茹治阿汤治疗阿尔茨海默病的临床研究[J].哈尔滨医药,2008,28(5)：41-42.
[59]董桂英,赵世珂,郭立华,等.清脑颐智灵治疗阿尔茨海默病60例临床观察[J].中西医结合心脑血管病杂志,2003,1(4)：236.
[1]盛树力.老年性痴呆及相关疾病[M].北京：科学技术文献出版社,2006.43-44.
[2]盛树力.老年性痴呆发病机理研究进展和药物治疗未来战略[J].中国医学科学院学报,2004,26(2)：101-103.
[3]郑隽,王永红.阿尔茨海默病治疗的研究进展[J].重庆医科大学学报,2007,32(增刊)：30-32.
[4]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”与轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11)：4-5.
[5]李浩,姚明江,赵文明,等.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1)：25-30.
[6]李浩,刘剑刚,姚明江,等.还脑益聪方对老龄认知障碍大鼠脂质代谢和海马内质网Ap相关结合蛋白表达的影响[J].中国中医基础医学杂志,2009,15(5)：354-357.
[7]姚明江,刘剑刚,李浩,等.还脑益聪方对早期认知功能障碍大鼠血浆P-选择素、血浆纤溶酶原激活物抑制剂和血液流变学指标的影响[J].中国微循环,2009,13(4)：254-258.
[8]李浩,姚明江,徐立,等.还脑益聪方对认知功能障碍大鼠认知功能及海马Bc1-2,Bax蛋白表达的影响[J].中国中药杂志,2009,34(20)：2622-2625.
[9]Zhang YW, Xu H. Molecular and cellular mechanisms for Alzheimer's disease:understanding APP metabolism[J]. Curr Mol Med,2007,7(7):687-696.
[10]马永兴,俞卓伟.现代痴呆学[M].北京：科学技术文献出版社,2008,274.
[11]Dewachter I, vanDorpe J, Spittaels K, et al. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin 1 on amyloid biochemistry and pathology APP/London mice[J]. Exp Gerontol,2000,35(627):831-841.
[12]秦川,朱华,常洋,等.阿尔茨海默症转基因小鼠的初步行为学评价[J].上海实验动物科学,2000,20(4)：210-211.
[13]黄澜,朱华,高虹,等.不同月龄人App老年痴呆病转基因小鼠行为学观察比较[J].中国老年性杂志,2004,24(12)：1185-1186.
[14]秦川,朱华,张兵林,等.阿尔茨海默病转基因动物模型脑组织病理学及免疫组化研究[J].中国实验动物学报,2000,8：213-217.
[15]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[16]White AM, Mattews DB, Best PJ. Ethanol, memory, and hippocampal function:a review of recent findings[J]. Hippocampus,2002,10(1):88-93.
[17]邢颖,张兰,李林.参乌胶囊抑制阿尔茨海默病模型小鼠脑内p-淀粉样肽生成的机制研究[J].中国老年学杂志,2006,26(7)：924-925.
[18]徐意.金思维提取物对AD模型鼠脑内p淀粉样肽及神经可塑性的影响[D]北京中医药大学,2006.
[19]邢颖,张兰,李林.参乌胶囊对APP转基因小鼠学习记忆能力及脑p-淀粉样肽含量的影响[J]中国康复理论与实践,2005,11(5)：324-326.
[20]Granic I, Dolga AM, Nijholt IM, et al. Inflammation and NF-κB in Alzheimer's Disease and Diabetes[J]. Journal of Alzheimer's Disease,2009,16:809-821.
[21]Paris D, Patel N, Quadros A, et al. Inhibition of Abeta production by NF-kappaB inhibitors[J]. Neurosci Lett,2007,415(1):11-16.
[22]Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in beta-amyloid-treated C6 glioma cells[J].Int J Mol Med,2006, 17(6):1069-1075.
[23]Jiang QG, Heneka M, Landreth GE. The Role of Peroxisome Proliferator-Activated Receptor-γ (PPARy) in Alzheimer's Disease[J]. CNS Drugs,2008,22(1):1-14.
[24]王英杰.旋覆花素对阿尔茨海默病的干预及其机制的实验研究[D].河北医科大学,2008.
[25]Moreira PI, Santos MS, Oliveira CR, et al. Alzheimer Disease and the Role of Free Radicals in the Pathogenesis of the Disease[J]. CNS & Neurological Disorders-Drug Targets,2008, 7(1):3-10.
[26]徐青,孙强三,王晓红,等.升黄益智方对痴呆模型小鼠脑组织SOD活性的影响[J].中国老年学杂志,2007,27(8)：734-735.
[27]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[28]李梅,林来祥,徐淑梅.H102对APP转基因小鼠胆碱能系统及自由基的影响[J].中国新药与临床杂志,2009,28(2)：106-109.
[29]Hamel E, Nicolakakis N, Aboulkassim T, et al. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease[J]. Exp Physiol,2008,93(1):116-120.
[30]邢颖,张兰,李林.二苯乙烯苷对APP转基因小鼠学习记忆能力和脑内β淀粉样肽表达的影响[J].中国新药杂志,2006,15(7)：510-513.
[31]杨小燕.制何首乌多糖对痴呆模型小鼠学习记忆能力及脑内酶活性的影响[J].药学进展,2005,29(12)：557-559.
[32]余上才,李晓玉.人参皂甙及β淀粉样蛋白对大鼠神经胶质瘤C6细胞产生前炎性细胞因子的影响[J].中国药理学会通讯,2000,17(4)：18.
[33]李玮,李林,褚燕琦,等.人参皂甙对β淀粉样蛋白诱导THP-1单核细胞-氧化氮合酶和-氧化氮的影响[J].中国神经免疫学和神经病学杂志,2006,13(2)：94-96.
[34]厉曙光,白莉华,王力强,等.人参对果蝇寿命的影响及其抗氧化作用[J].卫生研究,2008,37(1)：104-105.
[35]李彩虹,周克元.黄连活性成分的作用及机制研究进展[J].时珍国医国药,2010,21(2)：466-468.
[36]方青,詹小萍,莫剑翎,等.黄连解毒汤对AD大鼠的治疗作用及对细胞因子含量的影响[J].中国中药杂志,2004,29(6)：575-577.
[37]乔丽,林娜.黄连抗氧化作用的研究进展[C].第三届国际传统医药大会文集,2004：273.