益智汤对APP695转基因小鼠的治疗作用及其机理研究
|
摘要
阿尔茨海默病(AD)是一种常见的中枢神经系统退行性疾病,其主要病理特征为脑内β-淀粉样蛋白(Aβ)沉积形成老年斑(SP)和神经原纤维缠结(NFT),并伴有突触和神经元丢失等,严重损害认知功能,造成患者生活自理能力障碍和精神行为异常。研究表明老年斑的主要成分是Aβ, Aβ具有神经毒性,其在脑实质内沉积是AD发病的关键病理机制。中医理论认为AD发病由于肾虚髓亏,痰浊阻窍,故多用补肾填髓、化浊开窍法来治疗AD。益智方由淫羊藿、西洋参、枸杞、石菖蒲、天麻、川芎等6味药组成,方中淫羊藿、西洋参、枸杞补肾填髓；天麻、石菖蒲、川芎化浊开窍。本实验通过益智汤对APP695转基因小鼠的治疗作用环节及其机理研究,揭示补肾填髓、化浊开窍法治疗AD的作用机制,为中医临床治疗AD提供实验依据和增加新的内涵。
本实验分为两部分：
第一部分为整体实验,以13月龄APP695转基因小鼠为动物模型,随机分为模型组、益智汤治疗组,同月龄未经转基因处理的C57BL/6J小鼠做为正常对照组。益智汤组小鼠每天根据体重以益智汤(1ml/100g)灌胃,模型组和正常组给予等体积蒸馏水灌胃。益智汤治疗3个月后：(1)使用电迷宫、水迷宫检测各组小鼠学习记忆能力；(2)使用免疫组化技术和计算机图像分析技术测定各组小鼠大脑皮层、海马APP、Aβ1-40、Aβ1-42、Caspase3的表达情况；(3)应用ELISA技术定量测定各组小鼠脑组织和脑脊液Aβ1-42的浓度；(4)使用光镜和电镜观察各组小鼠脑组织的一般病理变化和超微结构病变；(5)末端转移酶介导的原位缺口末端标记染色(Tune1)法观察各组小鼠脑组织神经细胞凋亡情况。
第二部分为离体实验,选取体外培养8天的胎鼠大脑皮质神经元,加入不同浓度已经老化处理的Aβ25-35(5、10、20及40μmol/L)作用后,MTT比色法和LDH漏出量检测各组神经细胞活力和细胞膜功能的影响,倒置显微镜下观察神经元形态变化,来选择合适浓度老化处理的Aβ25-35复制AD细胞模型。模型组细胞加入益智汤含药大鼠血清,选择相同的观察指标,观察益智汤大鼠血清对Aβ25-35损伤神经元的保护作用。
主要实验结果如下：
1.益智汤可改善APP695转基因小鼠行为学习和记忆能力
Y型电迷宫显示模型组需要学习达标次数明显多于正常组,且记忆达标次数明显低于正常组(P＜0.01)。中药组所需达标次数少于模型组(P＜0.05),记忆能力明显改善(P＜0.01)。水迷宫结果显示模型组和中药组潜伏期多于正常组,进入盲端次数也多于正常组,与正常组有显著差异(P＜0.01,)。与模型组相比,中药组的潜伏期缩短,且进入盲端次数减少(P＜0.05)。说明16月龄APP695转基因小鼠学习记忆能力比正常对照组明显下降,较好地模拟了AD的行为学特征。中药益智汤能改善APP转基因模型小鼠的学习和记忆能力。
2.益智汤可降低APP695转基因小鼠脑组织内APP、Aβ1-40和Aβ1-42的表达
免疫组化结果显示模型组皮质和海马CA1区APP、Aβ1-40和Aβ1-42阳性神经细胞较正常组明显增加,且染色-加深,二者相比有显著差异。与模型组相比,中药组小鼠皮质和海马CA1区APP、Aβ1-40和Aβ1-42的阳性细胞较少,且着色变浅,二者相比有显著差异。ELISA试剂盒定量测定模型组小鼠脑组织和脑脊液中Aβ1-42的含量明显高于正常组,与正常组相比有极显著性差异。中药组小鼠脑组织和脑脊液中Aβ1-42的含量较模型组明显下降,说明益智汤治疗可以降低模型组小鼠脑组织APP、Aβ1-40和Aβ1-42的表达。
3.益智汤可减轻APP695转基因小鼠脑组织超微结构的损伤
光镜观察正常组小鼠大脑皮层组织结构清楚,神经细胞形态结构正常。而模型组小鼠大脑皮层和海马CA1区组织结构紊乱,神经元胞体缩小,胶质细胞增生；微血管管壁有炎性细胞分布,血管壁不整齐。中药组细胞排列较模型组整齐,形态较正常。电镜观察正常组大脑皮层神经元细胞膜完整清晰,核浆比例大,核内染色质分布均匀；细胞质内细胞器丰富,线粒体、突触结构清晰；有髓神经纤维的髓鞘连续、完整、均匀。模型组小鼠大脑神经元细胞膜部分模糊不清,细胞核膜内褶,染色质边聚；细胞质内细胞器减少,各级溶酶体及脂褐素增加；线粒体肿胀、嵴断裂、空泡样变,部分突触变性,突触前后膜及间隙模糊不清；有髓纤维髓鞘破碎不连续；毛细血管不规则,呈现局部管壁增厚。中药组超微结构病变比模型组减轻。
4.益智汤减少APP695转基因小鼠脑组织的细胞凋亡
免疫组化结果显示模型组小鼠脑组织Caspase3阳性细胞数量明显多于正常对照组,着色深度也强于正常对照组；而益智汤治疗组Caspase3阳性细胞数量较模型组较少,着色强度也弱于模型组。Tune1法显示模型组小鼠皮层、海马部位有较多Tune1强阳性细胞,说明模型组小鼠脑组织出现较多凋亡细胞。与模型组比较,中药组Tune1强阳性细胞明显减少,显示中药益智汤治疗可减少模型组小鼠脑组织Caspase3的表达及神经细胞的凋亡。
5.益智汤可以减少Aβ对体外培养神经细胞的毒性作用
培养胎鼠大脑皮质神经元细胞贴壁良好,分布均匀,结构清晰,突触间联系密切。加入Aβ25-35(5、10、20及40μmol/L)24h后,细胞生长状态不良,细胞肿胀变性,MTT检测细胞活性下降、LDH漏出率增加,随着Aβ25-35浓度的增加,细胞活性明显降低,LDH漏出率也明显增加,显示了Aβ25-35的毒性作用。选用10μmol/LAβ25-35复制AD细胞模型,加入益智汤治疗大鼠血清后,可以明显提高模型组细胞活力、降低LDH漏出率,改善细胞形态学异常。
结论
APP695转基因小鼠出现学习记忆能力减退,脑组织APP及Aβ表达增高,出现超微结构的病理改变及神经细胞凋亡,是较为理想的AD模型动物。益智汤可以降低模型组小鼠脑组织APP及Aβ的表达水平,改善其超微结构病理变化及抑制脑组织神经细胞凋亡,这是其改善APP695转基因小鼠学习记忆能力的基础。Aβ在脑微血管壁沉积,损伤血脑屏障,加重了Aβ的毒性作用,益智汤可以减轻血脑屏障的损伤。同时益智汤大鼠血清可以直接抑制Aβ的细胞毒性,发挥神经保护作用。以上结果说明益智汤通过多靶点减轻Aβ的毒性作用发挥神经保护功能,中药补肾填髓、化浊开窍法治疗AD具有实验依据。
Alzheimer disease(AD) is a kind of degenerative disease of central nervous system, the major pathological changes in AD are the formation of senile plaques(SP), neurofibrillary tangles(NFT) and loss of synapase and neurons in the cerebral cortex and subcortical structure, Which can severely impair the cognitive function and cause psychical and behavioral abnormality of the patient. The plaques are composed primarily of a small protein called amyloid-beta (Aβ). Aβhas toxicities to neurons and play important role in neurodegeneration and associated with cognitive and behavioral abnormalities. The evidence shows that intraparenchymal deposition of Aβis the major pathological hallmarks and plays a crucial part of the pathogenesis in AD. Traditional Chinese Medicine (TCM) considers that AD occurs in the brain and is closely connected with the deficiency of kidney and excess in superficiality in terms of its pathogenesis. Reinforcing the kidney to replenish marrow, removing blood and phlegm stasis to enrich the brain are the regular therapies. YiZhi fang is mainly composed of Herba Epimedii(Yinyanghuo), Panax quinquefolium(Xiyangshen), Barbary Wolfberry Fruit(GouQi), Rhizoma(Chuanxiong), Tall Gastrodia Tuber(Tianma) and Acorus tatarinowii Schott(Shichangpu), Which has the function of invigorating kidney to replenish marrow and removing phlegm and blood stasis to enrich the brain. The experiment focuses on the curative mechanism of YiZhi decoction to APP695 transgenic mice and provides a scientific ground and theoretical basis in clinical applications.
Materials and Methods:
1. Experimental study of the protective effect and its mechanism of YiZhi decoction on APP695 transgenic mice:
APP695 transgenic mice (13 months old) were randomly divided into model group and YiZhidecoction group, and negative transgenic mice (C57BL/6J) were included into normal group. The mice in YiZhi decoction group were given intragastrically YiZhi decoction (0.1g/kg) for 3 months, and the model group and normal group were given equal quantity of distilled water. (1)The learning and memory behavior of mice were examined by using Y-type electric maze test and LashleyⅢwater maze test. (2) Applying immunohistochemical technique, the expressions of APP, Aβ1-40, Aβ1-42 and Caspase3 in mouse cerebral cortex and hippocampal CA1 were observed by light microscope, using Image analysis their integral optical density in all group. (3)The changes of cell morphology were detected by HE stain and were observed by light microscope, the ultrastructure in cerebral cortex of the mice was observed by the transmission electronic microscope. (4)The levels of Aβ1-42 in cerebrospinal fluid(CSF) by using ELISA Assay Kit. (5)Cerebral neurocyte apoptosis in all group were detected with Terminal deoxynucleotidel transferase mediated uridine nucleotide end labeling(TUNEL).
2. Experimental study of the YiZhi decoction rat serum on primary cultured neural cells induced by Aβ25-35:
The primary cultured fetal rat cortical neurons were growth for 8 days. The neurons were treated with aggregated Aβ25-35 with different concentration for 24h. The morphologic changes of fetal rat cortical neurons induced by Aβ25-35 were observed by light microscope. Using MTT assay detected the changes of vitality of cells and detected the leakage of LDH. And By using the same means, YiZhi decoction rat serum as a protective effect, we also detected the survival rate and the leakage of LDH in all groups of primary cultured fetal rat cortical neuron induced by Aβ25-35 and YiZhi decoction rat serum, to explore the protective effect of YiZhi decoction rat serum on damage induced by Aβ25-35.
Objectives:
1. YiZhi decoction can improve learning and memory capacity of the model mice:
The results of Y-type electric maze test showed that the number used to indicate learning ability increased and the number used to indicate memory ability decreased in model group as compared with normal group (P<0.01), while the number used to indicate learning ability decreased and the number used to indicate memory ability increased in YiZhi decoction group as compared with model group. The results of Lashley III water maze test showed that the numbers of entering to blind-ending and lengthened latency in model group were more and longer than those in normal group, but those in YiZhi decoction group were considerably fewer and shorter than those in model group. The two means indicate that APP695 transgenic mice has learning and memory deficit and coincide with AD clinical feature, YiZhi decoction can improve learning and memory capacity of the model mice.
2. YiZhi decoction can down-regulate the expressions of APP, Aβ1-40 and Aβ1-42 in APP695 transgenic mice:
The number of APP, Aβ1-40 and Aβ1-42 positive cell and the degree of staining by their antibody in the cortex and hippocampal CA1 in the model group were higher than those in the normal group, using Image analysis their integral optical density (IOD). The levels of APP, Aβ1-40 and Aβ1-42 expression in the cortex and hippocampal CA1 of the model group obviously increased as compared with the normal group(P<0.01). the expression level of APP, Aβ1-40 and Aβ1-42 in YiZhi dectaion group were significantly lower than those in the model group(P<0.05). The levels of Aβ1-42 in cerebrospinal fluid(CSF) of model group were significantly higher than that in the normal group and YiZhi decoction group by using ELISA assay kit((P<0.05). The results indicate YiZhi decoction can down-regulate the level of APP, Aβ1-40 and Aβ1-42 in APP695 transgenic mice.
3. YiZhi decotaion can relieve brain tissue morphological changes in APP695 transgenic mice:
By the light microscope the modality configuration of cells in the Cerebral cortex and hippocampal CA1 in the normal group were normal, the neurons had regular arrangement with clear edges and obvious nucleus. But in model group the neurons had irregular arrangement and the edge of many cells was unclear, and there were infiltration of inflammatory cells in blood vessel walls, some neurons were atrophied; and those changes in the YiZhi decoction group were better than those in the model group, YiZhi decoction could improve brain tissue morphological changes in APP695 transgenic mice.
By the electron microscope in normal group mice the cell in cerebral cortex were normal, the nucleus was round and big, the normal and abnormal chromatin was obvious, the configurations of endoplasmic reticulum, mitochondrion and synapses were also normal, both presynaptic and postsynaptic membranes were clear. In model group, the cells were atrophied and dwindled with obvious borderline, the swollen, disrupted mitochondria, active microglia, degenerative synaptic structure and disarranged microtubule were frequently found, the presynaptic and postsynaptic membranes were illegible; cell organelles reduced but the deposition of lipofuscin granules increased, the basement membranes of capillaries was irregular and had some deposits; Myelin sheaths were loose, part of myelin fragments completely separated, microtubule and microfilaments showed particle dissolution. These pathological changes in the brain of YiZhi decoction treat group mice were not so apparent and were similar to model group.
4. YiZhi decoction can decrease cerebral neurocyte apoptosis in APP695 transgenic mice to protect cerebral neurocyte:
The number of Caspase3 positive cell and the degree of staining by Caspase3 antibody increased in the brain of model group as compared with the normal group(P<0.01). The expression level of Caspase3 in YiZhi decotaion group was significantly lower than that in the model group (P<0.05). The TUNEL positive cells in model group increased than those in normal group(P<0.01). The TUNEL positive cell decreased in YiZhi dectoaion group than that in model group. The results indicate YiZhi deoctaion can decrease cerebral neurocyte apoptosis in APP695 transgenic mice to protect cerebral neurocyte.
5 YiZhi decoction rat serum can protect the primary cultured neural cells from the damage induced by Aβ25-35:
The primary cultured fetal rat cortical neuron were performed with Aβ25-35 (5,10,20, 40μmol/L) for 24 hours, the growth state is bad. The activity of cultured neurons were decreased and LDH leakage increased in culture solution, and the cell viability decreased gradually when the concentration of Aβ25-35 raised up, there was significantly difference between model group and normal control group(P＜0.01). using 10μmol/L Aβ25-35 to made AD model cells, added YiZhi decoction rat serum, The activity of cultured neurons were higher in YiZhi decoction group than that in Aβ25-35 group, the growth state is good. The activity of nerve cells increased and LDH activity decreased by comparison with the experimental control group, which indicate that the YiZhi decoction rat serum could protect the cells from the damage induced by Aβ25-35 through abatting Aβnerotoxicity.
Conclusion:
APP695 transgenic mice has learning and memory deficit, increase the level of APP and Aβexpression, and has cerebral pathological changes and neurocyte apoptosis in brain, so it is a good animal model for AD. YiZhi decoction can regulate the level of APP and Aβ, can relieve cerebral pathological changes and decrease cerebralneurocyte apoptosis to protect cerebral neurocyte. That is the basement to improve learning and memory ability. YiZhi decoction rat serum could protect the cells from the damage induced by Aβ25-35. So YiZhi decoction can antagonize toxicity of Aβon neuron and protect nerve cell. The study provides experimental support for reinforcing the kidney to replenish marrow, removing blood and phlegm stasis to provide a scientific ground for clinical treatment of AD.
本实验分为两部分：
第一部分为整体实验,以13月龄APP695转基因小鼠为动物模型,随机分为模型组、益智汤治疗组,同月龄未经转基因处理的C57BL/6J小鼠做为正常对照组。益智汤组小鼠每天根据体重以益智汤(1ml/100g)灌胃,模型组和正常组给予等体积蒸馏水灌胃。益智汤治疗3个月后：(1)使用电迷宫、水迷宫检测各组小鼠学习记忆能力；(2)使用免疫组化技术和计算机图像分析技术测定各组小鼠大脑皮层、海马APP、Aβ1-40、Aβ1-42、Caspase3的表达情况；(3)应用ELISA技术定量测定各组小鼠脑组织和脑脊液Aβ1-42的浓度；(4)使用光镜和电镜观察各组小鼠脑组织的一般病理变化和超微结构病变；(5)末端转移酶介导的原位缺口末端标记染色(Tune1)法观察各组小鼠脑组织神经细胞凋亡情况。
第二部分为离体实验,选取体外培养8天的胎鼠大脑皮质神经元,加入不同浓度已经老化处理的Aβ25-35(5、10、20及40μmol/L)作用后,MTT比色法和LDH漏出量检测各组神经细胞活力和细胞膜功能的影响,倒置显微镜下观察神经元形态变化,来选择合适浓度老化处理的Aβ25-35复制AD细胞模型。模型组细胞加入益智汤含药大鼠血清,选择相同的观察指标,观察益智汤大鼠血清对Aβ25-35损伤神经元的保护作用。
主要实验结果如下：
1.益智汤可改善APP695转基因小鼠行为学习和记忆能力
Y型电迷宫显示模型组需要学习达标次数明显多于正常组,且记忆达标次数明显低于正常组(P＜0.01)。中药组所需达标次数少于模型组(P＜0.05),记忆能力明显改善(P＜0.01)。水迷宫结果显示模型组和中药组潜伏期多于正常组,进入盲端次数也多于正常组,与正常组有显著差异(P＜0.01,)。与模型组相比,中药组的潜伏期缩短,且进入盲端次数减少(P＜0.05)。说明16月龄APP695转基因小鼠学习记忆能力比正常对照组明显下降,较好地模拟了AD的行为学特征。中药益智汤能改善APP转基因模型小鼠的学习和记忆能力。
2.益智汤可降低APP695转基因小鼠脑组织内APP、Aβ1-40和Aβ1-42的表达
免疫组化结果显示模型组皮质和海马CA1区APP、Aβ1-40和Aβ1-42阳性神经细胞较正常组明显增加,且染色-加深,二者相比有显著差异。与模型组相比,中药组小鼠皮质和海马CA1区APP、Aβ1-40和Aβ1-42的阳性细胞较少,且着色变浅,二者相比有显著差异。ELISA试剂盒定量测定模型组小鼠脑组织和脑脊液中Aβ1-42的含量明显高于正常组,与正常组相比有极显著性差异。中药组小鼠脑组织和脑脊液中Aβ1-42的含量较模型组明显下降,说明益智汤治疗可以降低模型组小鼠脑组织APP、Aβ1-40和Aβ1-42的表达。
3.益智汤可减轻APP695转基因小鼠脑组织超微结构的损伤
光镜观察正常组小鼠大脑皮层组织结构清楚,神经细胞形态结构正常。而模型组小鼠大脑皮层和海马CA1区组织结构紊乱,神经元胞体缩小,胶质细胞增生；微血管管壁有炎性细胞分布,血管壁不整齐。中药组细胞排列较模型组整齐,形态较正常。电镜观察正常组大脑皮层神经元细胞膜完整清晰,核浆比例大,核内染色质分布均匀；细胞质内细胞器丰富,线粒体、突触结构清晰；有髓神经纤维的髓鞘连续、完整、均匀。模型组小鼠大脑神经元细胞膜部分模糊不清,细胞核膜内褶,染色质边聚；细胞质内细胞器减少,各级溶酶体及脂褐素增加；线粒体肿胀、嵴断裂、空泡样变,部分突触变性,突触前后膜及间隙模糊不清；有髓纤维髓鞘破碎不连续；毛细血管不规则,呈现局部管壁增厚。中药组超微结构病变比模型组减轻。
4.益智汤减少APP695转基因小鼠脑组织的细胞凋亡
免疫组化结果显示模型组小鼠脑组织Caspase3阳性细胞数量明显多于正常对照组,着色深度也强于正常对照组；而益智汤治疗组Caspase3阳性细胞数量较模型组较少,着色强度也弱于模型组。Tune1法显示模型组小鼠皮层、海马部位有较多Tune1强阳性细胞,说明模型组小鼠脑组织出现较多凋亡细胞。与模型组比较,中药组Tune1强阳性细胞明显减少,显示中药益智汤治疗可减少模型组小鼠脑组织Caspase3的表达及神经细胞的凋亡。
5.益智汤可以减少Aβ对体外培养神经细胞的毒性作用
培养胎鼠大脑皮质神经元细胞贴壁良好,分布均匀,结构清晰,突触间联系密切。加入Aβ25-35(5、10、20及40μmol/L)24h后,细胞生长状态不良,细胞肿胀变性,MTT检测细胞活性下降、LDH漏出率增加,随着Aβ25-35浓度的增加,细胞活性明显降低,LDH漏出率也明显增加,显示了Aβ25-35的毒性作用。选用10μmol/LAβ25-35复制AD细胞模型,加入益智汤治疗大鼠血清后,可以明显提高模型组细胞活力、降低LDH漏出率,改善细胞形态学异常。
结论
APP695转基因小鼠出现学习记忆能力减退,脑组织APP及Aβ表达增高,出现超微结构的病理改变及神经细胞凋亡,是较为理想的AD模型动物。益智汤可以降低模型组小鼠脑组织APP及Aβ的表达水平,改善其超微结构病理变化及抑制脑组织神经细胞凋亡,这是其改善APP695转基因小鼠学习记忆能力的基础。Aβ在脑微血管壁沉积,损伤血脑屏障,加重了Aβ的毒性作用,益智汤可以减轻血脑屏障的损伤。同时益智汤大鼠血清可以直接抑制Aβ的细胞毒性,发挥神经保护作用。以上结果说明益智汤通过多靶点减轻Aβ的毒性作用发挥神经保护功能,中药补肾填髓、化浊开窍法治疗AD具有实验依据。
Alzheimer disease(AD) is a kind of degenerative disease of central nervous system, the major pathological changes in AD are the formation of senile plaques(SP), neurofibrillary tangles(NFT) and loss of synapase and neurons in the cerebral cortex and subcortical structure, Which can severely impair the cognitive function and cause psychical and behavioral abnormality of the patient. The plaques are composed primarily of a small protein called amyloid-beta (Aβ). Aβhas toxicities to neurons and play important role in neurodegeneration and associated with cognitive and behavioral abnormalities. The evidence shows that intraparenchymal deposition of Aβis the major pathological hallmarks and plays a crucial part of the pathogenesis in AD. Traditional Chinese Medicine (TCM) considers that AD occurs in the brain and is closely connected with the deficiency of kidney and excess in superficiality in terms of its pathogenesis. Reinforcing the kidney to replenish marrow, removing blood and phlegm stasis to enrich the brain are the regular therapies. YiZhi fang is mainly composed of Herba Epimedii(Yinyanghuo), Panax quinquefolium(Xiyangshen), Barbary Wolfberry Fruit(GouQi), Rhizoma(Chuanxiong), Tall Gastrodia Tuber(Tianma) and Acorus tatarinowii Schott(Shichangpu), Which has the function of invigorating kidney to replenish marrow and removing phlegm and blood stasis to enrich the brain. The experiment focuses on the curative mechanism of YiZhi decoction to APP695 transgenic mice and provides a scientific ground and theoretical basis in clinical applications.
Materials and Methods:
1. Experimental study of the protective effect and its mechanism of YiZhi decoction on APP695 transgenic mice:
APP695 transgenic mice (13 months old) were randomly divided into model group and YiZhidecoction group, and negative transgenic mice (C57BL/6J) were included into normal group. The mice in YiZhi decoction group were given intragastrically YiZhi decoction (0.1g/kg) for 3 months, and the model group and normal group were given equal quantity of distilled water. (1)The learning and memory behavior of mice were examined by using Y-type electric maze test and LashleyⅢwater maze test. (2) Applying immunohistochemical technique, the expressions of APP, Aβ1-40, Aβ1-42 and Caspase3 in mouse cerebral cortex and hippocampal CA1 were observed by light microscope, using Image analysis their integral optical density in all group. (3)The changes of cell morphology were detected by HE stain and were observed by light microscope, the ultrastructure in cerebral cortex of the mice was observed by the transmission electronic microscope. (4)The levels of Aβ1-42 in cerebrospinal fluid(CSF) by using ELISA Assay Kit. (5)Cerebral neurocyte apoptosis in all group were detected with Terminal deoxynucleotidel transferase mediated uridine nucleotide end labeling(TUNEL).
2. Experimental study of the YiZhi decoction rat serum on primary cultured neural cells induced by Aβ25-35:
The primary cultured fetal rat cortical neurons were growth for 8 days. The neurons were treated with aggregated Aβ25-35 with different concentration for 24h. The morphologic changes of fetal rat cortical neurons induced by Aβ25-35 were observed by light microscope. Using MTT assay detected the changes of vitality of cells and detected the leakage of LDH. And By using the same means, YiZhi decoction rat serum as a protective effect, we also detected the survival rate and the leakage of LDH in all groups of primary cultured fetal rat cortical neuron induced by Aβ25-35 and YiZhi decoction rat serum, to explore the protective effect of YiZhi decoction rat serum on damage induced by Aβ25-35.
Objectives:
1. YiZhi decoction can improve learning and memory capacity of the model mice:
The results of Y-type electric maze test showed that the number used to indicate learning ability increased and the number used to indicate memory ability decreased in model group as compared with normal group (P<0.01), while the number used to indicate learning ability decreased and the number used to indicate memory ability increased in YiZhi decoction group as compared with model group. The results of Lashley III water maze test showed that the numbers of entering to blind-ending and lengthened latency in model group were more and longer than those in normal group, but those in YiZhi decoction group were considerably fewer and shorter than those in model group. The two means indicate that APP695 transgenic mice has learning and memory deficit and coincide with AD clinical feature, YiZhi decoction can improve learning and memory capacity of the model mice.
2. YiZhi decoction can down-regulate the expressions of APP, Aβ1-40 and Aβ1-42 in APP695 transgenic mice:
The number of APP, Aβ1-40 and Aβ1-42 positive cell and the degree of staining by their antibody in the cortex and hippocampal CA1 in the model group were higher than those in the normal group, using Image analysis their integral optical density (IOD). The levels of APP, Aβ1-40 and Aβ1-42 expression in the cortex and hippocampal CA1 of the model group obviously increased as compared with the normal group(P<0.01). the expression level of APP, Aβ1-40 and Aβ1-42 in YiZhi dectaion group were significantly lower than those in the model group(P<0.05). The levels of Aβ1-42 in cerebrospinal fluid(CSF) of model group were significantly higher than that in the normal group and YiZhi decoction group by using ELISA assay kit((P<0.05). The results indicate YiZhi decoction can down-regulate the level of APP, Aβ1-40 and Aβ1-42 in APP695 transgenic mice.
3. YiZhi decotaion can relieve brain tissue morphological changes in APP695 transgenic mice:
By the light microscope the modality configuration of cells in the Cerebral cortex and hippocampal CA1 in the normal group were normal, the neurons had regular arrangement with clear edges and obvious nucleus. But in model group the neurons had irregular arrangement and the edge of many cells was unclear, and there were infiltration of inflammatory cells in blood vessel walls, some neurons were atrophied; and those changes in the YiZhi decoction group were better than those in the model group, YiZhi decoction could improve brain tissue morphological changes in APP695 transgenic mice.
By the electron microscope in normal group mice the cell in cerebral cortex were normal, the nucleus was round and big, the normal and abnormal chromatin was obvious, the configurations of endoplasmic reticulum, mitochondrion and synapses were also normal, both presynaptic and postsynaptic membranes were clear. In model group, the cells were atrophied and dwindled with obvious borderline, the swollen, disrupted mitochondria, active microglia, degenerative synaptic structure and disarranged microtubule were frequently found, the presynaptic and postsynaptic membranes were illegible; cell organelles reduced but the deposition of lipofuscin granules increased, the basement membranes of capillaries was irregular and had some deposits; Myelin sheaths were loose, part of myelin fragments completely separated, microtubule and microfilaments showed particle dissolution. These pathological changes in the brain of YiZhi decoction treat group mice were not so apparent and were similar to model group.
4. YiZhi decoction can decrease cerebral neurocyte apoptosis in APP695 transgenic mice to protect cerebral neurocyte:
The number of Caspase3 positive cell and the degree of staining by Caspase3 antibody increased in the brain of model group as compared with the normal group(P<0.01). The expression level of Caspase3 in YiZhi decotaion group was significantly lower than that in the model group (P<0.05). The TUNEL positive cells in model group increased than those in normal group(P<0.01). The TUNEL positive cell decreased in YiZhi dectoaion group than that in model group. The results indicate YiZhi deoctaion can decrease cerebral neurocyte apoptosis in APP695 transgenic mice to protect cerebral neurocyte.
5 YiZhi decoction rat serum can protect the primary cultured neural cells from the damage induced by Aβ25-35:
The primary cultured fetal rat cortical neuron were performed with Aβ25-35 (5,10,20, 40μmol/L) for 24 hours, the growth state is bad. The activity of cultured neurons were decreased and LDH leakage increased in culture solution, and the cell viability decreased gradually when the concentration of Aβ25-35 raised up, there was significantly difference between model group and normal control group(P＜0.01). using 10μmol/L Aβ25-35 to made AD model cells, added YiZhi decoction rat serum, The activity of cultured neurons were higher in YiZhi decoction group than that in Aβ25-35 group, the growth state is good. The activity of nerve cells increased and LDH activity decreased by comparison with the experimental control group, which indicate that the YiZhi decoction rat serum could protect the cells from the damage induced by Aβ25-35 through abatting Aβnerotoxicity.
Conclusion:
APP695 transgenic mice has learning and memory deficit, increase the level of APP and Aβexpression, and has cerebral pathological changes and neurocyte apoptosis in brain, so it is a good animal model for AD. YiZhi decoction can regulate the level of APP and Aβ, can relieve cerebral pathological changes and decrease cerebralneurocyte apoptosis to protect cerebral neurocyte. That is the basement to improve learning and memory ability. YiZhi decoction rat serum could protect the cells from the damage induced by Aβ25-35. So YiZhi decoction can antagonize toxicity of Aβon neuron and protect nerve cell. The study provides experimental support for reinforcing the kidney to replenish marrow, removing blood and phlegm stasis to provide a scientific ground for clinical treatment of AD.
引文
1 Blennow K, de LeonM J, Zetterberg H. Alzheimers disease. Lancet.2006,368 (9533): 387-403
2 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science.2002,297 (5580):353-356
3 Murphy MP,LeVine H 3rd. Alzheimer's Disease and the β-Amyloid Peptide. J Alzheimers Dis.2010,19 (1):311-23
4 E.Mohandas, V. Ra jmohan, B. Raghunath. Neurobiology of Alzheimer's disease. Indian J Psychiatry.2009,51 (1):55-61
5 Qi-Takahara Y,Morishima-Kawashima M, Tanimura Y, et al. Longer forms of amyloid beta protein:implications for the mechanism of intramembrane cleavage by gamma-secretase. The Journal of Neuroscience,2005,25 (2):436-445
6 Thinakaran G,Koo EH. Amyloid Precursor Protein Trafficking, Processing,and Function. J Biol Chem.2008 October31,283 (44):29615-29619
7 Zheng H, Koo EH. The amyloid precursor protein:beyond amyloid. Mol Neurodegener. 2006, Jul3; 1:5
8 Kim J,Onstead L, Randle S, et al.Abeta40 inhibits amyloid deposition in vivo. J Neurosci,2007,27:627-633
9 Luhrs T, Ritter C, Adrian M, et al.3D structure of Alzheimer's amyloid beta (1-42) fibrils. Proc Natl Acad Sci USA,2005, Nov 29,102 (48):17342-17347
10 Sgourakis NG, Yan Y.McCallum SA, et al.The Alzheimer's peptidesA β 40 and 42 adopt distinct conformations in water:a combinedMD/NMR study. J Mol Biol.2007, 368:1448-1457
11 Petkova AT, Leapman RD,Guo Z, et al. Self-propagating, molecularlevel polymorphism in Alzheimer's β-amyloid fibrils. Science,2005,307:262-265
12 Chiti F, Dobson CM. Protein misfolding, functional amyloid,and human disease. Annu Rev Biochem.2006,75:333-366
13 Sgourakis NG, Yan Y,McCallum SA,et al.The Alzheimer's peptides A P 40 and 42 adopt distinct conformations in water:a combined MD/NMR study. J Mol Biol.2007, 368(5):1448-1457
14 Gong Y, Chang L, Viola KL, Lacor PN, et al. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A.2003 Sep2; 100(18):10417-10422
15 Malito E,Hulse RE,Tang WJ. Amyloid beta-degrading cryptidases:insulin degrading enzyme, presequence peptidase, and neprilysin.Cell Mol Life Sci.2008 Aug;65(16):2574-2585
16 El-Amouri SS, Zhu H, Y,u J,Marr R, et al. Neprilysin:an enzyme candidate to slow the progression of Alzheimer's disease. Am J Pathol.2008 May; 172(5):1342-1354
17 Caccamo A, Oddo S, Sugarman MC,et al.Age and region dependent alterations in Abeta degrading enzymes:implications for Abeta induced disorders. Neurobiol Aging.2005,26 (5):645-654
18 Marr R A, Guan H, Rochenstein E, et al. Neprilysin Regulates amyloid Beta peptide levels. Journal of Molecular Neuroscience,2004,22 (1-2):5-11
19 de Tullio MB, Morelli L, Castano EM. The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme:a biological perspective. Prion.2008,2(2):51-56
20 Miller BC, Eckman EA, Sambamurti K, et al. Amyloid2beta peptide levels in brain are inversely correlated with insulysin activitylevels in vivo. Proc NatlAcad SciUSA,2003,100 (10):6221-6226
21 FarrisW,Mansourian S,Leissring MA, et al. Partial loss of function mutations in insulin degrading enzyme that induce diabetes aloimpair degradation of amyloid beta-protein. Am J Pathol,2004,164(4):1425-1434
22 Wang DS, Dickson DW,Malter JS. β-Amyloid Degradation and Alzheimer's Disease. Biomed Biotechnol.2006, (3):58406-58413
23 Jacobsen JS,Comery TA,Martone RL, et al. Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.Proc Natl Acad Sci USA.2008, 105(25):8754-8759
24 Yang YH, Liu CK. Angiotensin-converting enzyme gene in Alzheimer's disease. Tohoku J Exp Med.2008,215 (4):295-298
25 Hemming ML,Selkoe DJ,Farris W. Effects of prolonged angiotensin converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse'of Alzheimer disease. Neurobiol Dis.2007,26 (1):273-281
26 Jeynes B,Provias J.Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis.Curr Alzheimer Res.2008,5 (5):432-437
27 Judy A Cam, Guojun Bu. Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.Mol Neurodegener, 2006,1:8
28 Bu G, Cam J, Zerbinatti C. LRP in amyloid-beta production and metabolism. Ann N Y Acad Sci.2006,1086:35-53
29 Hert J. LRP:a bright beacon at the blood-brain barrier. J Glin Invest,2003, 112(10):1483-1485
30 Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzhermer's amyloid β-40 peptide from brain by LDL receptor related protein-1 at the blood brain barrier. J Clin Invest,2000,106(12):1489-1499
31 Laura B, Jaeger, Shinya Dohgu, et al.Testing the Neurovascular Hypothesis of Alzheimer's Disease:LRP-1 Antisense Reduces Blood-Brain Barrier Clearance, Increases Brain Levels of Amyloid-β Protein,and Impairs Cognition. Alzheimers Dis.2009 Jul; 17(3):553-70
32 Lue LF, Walker DG,Jacobson S, Sabbagh M. Receptor for advanced glycation end products:its role in Alzheimer's disease and other neurological diseases. Future Neurol.2009,4(2):167-177
33 Miller MC, Tavares R, Johanson CE,et al. Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease.Brain Res.2008,1230:273-280
34 Deane R,Du Yan S, Submamaryan RK,et al.RAGE mediates amyloid β peptide transport across the blood rain barrier and accumulation in brain. Nature.2003, 9(7):907-913
35 Zlokovic BV. New therapeutic targets in the neurovascular pathway in Alzheimer' s disease. Neurotherapeutics.2008,5 (3):409-414.
36 Lam FC,Liu R,Lu P,et al. beta-Amyloid efflux mediated by p-glycoprotein.J Neurochem,2001,76(4):1121-1128
37 Hartz AM,Miller DS,Bauer B. Restoring Blood-Brain Barrier P-glycoprotein Reduces Brain A{beta} in a Mouse Model of Alzheimer's Disease. Mol Pharmacol. 2010. [Epub ahead of print]
38 Hickman SE, Allison EK,El Khoury J.Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008,28(33):8354-8360
40 Murphy MP,LeVine H 3rd. Alzheimer's Disease and the β-Amyloid Peptide.J Alzheimers Dis.2010,19(1):311-323
41 Pearson HA, Peers C. Physiological roles for amyloid beta peptides. J Physiol. 2006,575(Pt1):5-10
42 Plant LD,Webster NJ,Boyle JP,et al.Amyloid beta peptide as a physiological modulator of neuronal 'A' -type- K+ current.Neurobiol Aging,2006,27 (11):1673-1683
4.3 Kamenetz F, Iomita T, Hsieh H, et al. APP processingand synaptic function. Neuron. 2003,37(6):925-937
44 Plant LD, Boyle JP, Smith IF,et al.The production of amyloid beta peptide is a critical requirement for the viability of central neurons.J Neurosci.2003, 23(13):5531-5535
45 Kayed R, Head E, Thompson JI, et al. Common structure of soluble amyloid oligomrrs implies common mechanism of pathogenesis. Science.2003,300:486-489
46 Walsh DM, Klyubin I,Fadeeva JV,et al.Naturally secreted olignmers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002,416(6880):535-539
47 Pike CJ,Cummings BJ, Cotman CW. beta-Amyloid induces neuritic dystrophy in vitro:similarities with Alzheimer pathology. Neuroreport.1992,3(9):769-772
48 Clifford PM, Zarrabi S,Siu G, et al.Abeta peptides can enter the brainthrough a defective blood-brain barrier and bind selectively to neurons. Brain Res,2007, 1142:223-236
49 Resende R,Pereira C, Agostinho P, et al. Susceptibility of hippocampalneurons to Abeta peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res.2007,1143:211-217
50 Akiyana H,Barger S, Barnum S, et al. Inflammation and Alzheimer's diseas. Neurobiol Aging.2000,21 (3):383-421
51 Walker DG, Link J, Lue L F, et al. Gene expression changes by amyloid beta peptide stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. Journal of Leukocyte Biology.2006,79(3):596-610
52 Giovannini MG, Scali C, Prosperi C, et al. Beta-amyloid induced in flammation and cholinergic hypofunction in the rat brain in vivo:in volvement of the p38 MAPK pathway. Neurobiol Dis,2002,11 (2):257-262
53 Hull M, Muksch B, Akundi RS, et al. Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostagland in E-2 release in primary midbrain astrocytes. Neurochemistry International,2006, 48 (8):663-672
54 Ho L, Qin WP,Stet ka BS, et al. Is there a future for cyclo-oxygenase inhibitors in Alzheimer's disease? CNS Drugs.2006,20(2):85-98
55 Tobinick E, Gross H,Weinberger A, et al.TNF-alpha modulation-for treatment of Alzheimer's disease:a 6-month pilot study. Med GenMed.2006,8(2):25
56 Varvel NH,Bhaskar K,Kounnas MZ,et,al. NSAIDs prevent,but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. 2009,119 (12): 3692-702
57 Simard AR,Soulet D,Gowing G,et al.Bone marrow derived microglia p lay a critical role in restricting senile p laque formation in Alzheimerps disease. Neuron.2006,49 (4):489-502
58 Floden AM, Combs CK. Beta amyloid stimulatesmurine postnataland adult microglia cultures in a unique manner. Neurosci,2006,26(17):4644-4648
59 Feiqi Zhu,Caiyun Qian. Berberine chloride increases the activation of microglia by inhibiting the expression of peroxisome proliferator activated receptor gamma in the rat model of Alzheimer's disease. Eur J Neurol, BMC Neurosci,2006,7:78
60 Wyss Coray T,Mucke L. Inflammation in neurodegenerative diseasea double-edged sword. Neuron,2002,35 (3):419-432
61 arnham KJ,Cappai R, Beyreuther K, et al. Delineating common molecular mechanisms in Alzheimer's and prion diseases. TrendsBiochem Sci,2006,31(8): 465-472
62 Sultana R, Perluigi M, Butterfield DA. Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impairment and animal models of AD:role of A-beta in pathogenesis.Acta Neuropathol.2009,118(1):131-150
63 Zilka N, Novak M. The tangled story of Alois Alzheimer. Bratisl Lek Listy,2006,107(9-10):343-345
64 Tanzi RE, Bertram, L. Twenty years of the Alzheime's disease amyloid hypothesis: a genetic perspective. Cell.2005,120(4):545-555
65 De Felice FG, Velasco PT, Lambert MP, et al.A β oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem,2007,282 (15): 11590-11601
66 Hossain S, Grande M, Ahmadkhanov G,et al. Binding of the Alzheimer amyloid beta-peptide to neuronal cell membranes by fluorescence correlation spectroscopy. Exp Mol Pathol,2007,82:169-174
67 Hashimoto M, Rockenstein E, Crews L, et al.Role of protein aggregationin mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromol Med,2003,4:21-36
68 Wallace MN,Geddes JG,Farquhar DA,et al. Nitric oxide synthase inreactive astrocytes adjacent to β-amyloid plaques. Exp Neurol,1997,144:266-272
69 ZHAO Lin, HE Miao,.JIN Wan-bao, et al:Vitamin E administration improves learning and memory deficits in modeling Alzheimer's disease. Chinese Journal of Clinical Pharmacology and Therapeutics.2009,14(1):25-31
70 Reix S,Mechawar N,Susin SA,et al. Expression of cortical and hippocampal apoptosis-inducing factor (AIF) in aging and Alzheimer's disease. Neurobiol Aging.2007,28(3):351-356
71 Patel JR, Brewer GJ.Age-related differences in NFkappaB translocation and Bcl-2/Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons.Exp Neurol.2008,213(1):93-100
72 Louneva N, Cohen JW,Han LY,et al.Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. Am J Pathol.2008,173 (5): 1488-1495
73 Raynaud F,Marcilhac A. Implication of calpain in neuronal apoptosis A possible regulation of Alzheimer's disease. Febs Journal.2006,273(15):3437-3443
74 Starr JM,Armitage P,Armitage P,et al. Blood-brain barrier permeability in Alzheimer's disease:a case-control MRI study. Psychiatry Res.2009,171 (3): 232-241
75 Petersen RC, Negash S. Mild cognitive impairment:an overview. CNS Spectr.2008, 13(1):45-53
76 Yu Yan, Zhou Liang,Xu Feng, et al.Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Nervous Diseases and Mental Health.2008, 8(6):411-413
77 Lustbader JW,Cirilli M, Lin C, et al. ABAD directly links A β to mitochondrial toxicity in Alzheimer's disease. Science.2004,304 (5669):448-452
78 Deshpande A,Mina E, Glabe C,et al. Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons.J Neurosci.2006,26 (22):6011-6018.
79 Lacor PN, Buniel MC, Furlow PW, et al.Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecularbasis for loss of connectivity in Alzheimer's disease. J Neurosci,2007,27 (4):796-807
80 Wahlstrom A, Hugonin L, Peralvarez-Marin A, et al. Secondary structure conversions of Alzheimer's Abeta(1-40) peptide induced by membrane mimicking detergents. FEBS J.2008,275(20):5117-5128
81 Yoshiike Y.Minai R,Matsuo Y,et al. Amyloid oligomer conformation in a group of natively folded proteins. PLoS One,2008,3 (9):e3235
82 Jacobsen JS,Wu CC,Redwine JM,et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. ProcNatl Acad Sci USA,2006, 103(13):5161-5166
1 Blennow K, de Leon MJ,Zetterberg H. Alzheimer's disease. Lancet.2006 Jul 29,368 (9533):387-403
2郑元元,孙兰.阿尔采末病非人灵长类动物模型.中国药理学通报.2005,21(6)：649-653
3 Teng E, Stefanacci L, Squire LR, Zola SM. Constrasting effects on discrimination learning after hippocampal lesions and conjoint hippocampal can duate lesions in monkeys. J Neurosci,2000,20(10):3853-3863
4 Iijima K, Liu HP, Chiang AS,et,al.Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila:a potential model for Alzheimer's disease. Proc.Natl Acad.Sci USA.2004,101 (17):6623-6628
5 Iijima-Ando K, Hearn SA,Shenton C, et, al. Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One.2009,4(12):e8310
6谢宁,宋琳莉,牛英才,等.老年性痴呆动物模型研究进展及其评价.实验动物与比较医学,Mar.2006,26(1)：,50-53
7杨春壮,马彦文,刘长.老年性痴呆动物模型优劣浅析.牡丹江医学院学报,2003,24(3)：53-55
8 Francesc XS, Javier GC,Marta R, et al. Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence accelerated mice SAMP-8. Experimental Gerontology.2006,41 (4):360-367
9周伟勤,毕明刚,杜冠.快速老化小鼠SAMP8研究进展.中国药理学通报,2009,25(5)：565-568
10Yan Wu,Zhang AQ, Wai MS,et al. Changes of apoptosis related proteins in hippocampus of SAM mouse in development and aging. Neurobiology of Aging.2006, 27(5):1-10
11楚晋,李林.D-半乳糖致脑老化动物模型及其机理.中国康复理论与实践,2003,9(9)：521-522
12郭宗君,金丽英,郭云良,等.三种化学物质诱发大鼠认知障碍：优化阿尔茨海默病模型的研究.中国临床康复,2004,8(25)：5266-5268
13李守民,王婷婷,胡艳丽,等.D-乳糖调控SD大鼠海马巯醇抗氧化物(酶)致衰老的作用研究.昆明医学院学报,2009,(5)：1-5
14 Qin Hong-bing, Yang Zhao-ye, Fan Yi-jiang, Zhu Qing. Establishment and evaluation of aging models induced by D-galactose in mice. Journal of Clinical Rehabilitative Tissue Engineering Research,2009,13, (7):1275-1278
15冀俊虎,董联玲,曹娟,等.红景天对阿尔茨海默病大鼠行为学和脑组织抗氧化能力的影响.中国中医药信息杂志,2009,16(2)：38-40
16廉洁.复方地黄对大鼠学习记忆及海马CA1区神经元突触超微结构改变的实验研究.中华中医药学刊,2007,25(7)：1482-1483
17 Talesa VN. Acetylcholinesterase in Alzheimer's disease. Mechanisms of Ageing and Development,2001,122(16):1961-1969
18 Sisodia SS,Martin LJ, Walker LC. Cellular and molecular biology of Alzheimer' s disease and animal models. Neuroimaging Clin N Am.1995,5(1):59-68
19 Van Groen, Thomas, Kadish,et al. Transgenic AD model mice, effects of potential Anti-AD treatments on inflammation andpathology. Brain Reasearch Reviews.2005, 48 (2):370-378
20隋承光,尹元琴,任常山.Alzhemier病动物模型的构建及其分子病理学的变化.中国老年医学杂志,2005,25(9)：1069-1071
21邱幸凡,王平,袁德培.犀脑益智方对大鼠胆破能系统的影响.中医药学刊,2006,24(8)：1399-1440
22陆珊,雷亚平,王蓬文,等.APP5肽类似物i65对老年性痴幕模型大鼠行为学及PSD95和Shankl表达的影响.中国神经免疫学和神经病学杂志,2007,14(4)：183-184
23 Scalic C, Prosperi C, Vannucchi MG,et al. Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug:implication in Alzheimer's disease.Eur J Neurosci,2000,12:1900-1912
24杨勇,马龙,周晓辉,等.一种新型阿尔茨海默病动物模型的建立.新疆医科大学学报,2005,28(5)：399-404
25许妍姬.刺五加对痴呆模型小鼠记忆障碍及脑组织单胺氧化酶活性改变的保护作用.中成药,2009,31(8)：1290-1291
26方芳,晏勇,冯占辉,等.多因素损伤的老年性痴呆动物模型的实验研究.垂庆医学,2007,36(2)：146-148
27杨勇,马龙,周晓辉,洪玉.一种新型阿尔茨海默病动物模型的建立.新疆医科大学学报,2005,28(5)：399-404
28高丽萍,程书珍,王晓梅,贾丽霞.铝诱导阿尔茨海默病大鼠模型的建立.广东医学,2008,29(11)：1798-1800
29 Qian YH, Liu Y,Hu HT,et al.The effects of the total saponin of Dipsacus asperoides on the damage of cultured neurons induced by β-amyloid protein25-35. AnatSci Int,2002,77 (3):196-200
30杨杰,刘勇,钱亦华,等.β-淀粉样蛋白诱导大鼠海马S100 β表达的作用及机制.西安交通大学学报(医学版),2004,8(5)：322-325
31聂晶,罗勇,黄燮南.淫羊藿苷对淀粉样β蛋白片段25-35所致大鼠学习记忆障碍的改善作用.中国药理学与毒理学杂志,2008,22(1)：31-37
32楚晋,叶翠飞,李林,张丽.二苯乙烯苷对D-淀粉样肽致痴呆模型小鼠行为及胆碱能功能的影响.基础医学与临床,2006,26(2)：197-198
33楚晋,李林.脑室灌注β-淀粉样肽致痴呆动物模型.中国药理学通报,2004,20(7)：827-829
34张媛媛,李晓红,王敏,王栋.阿托伐他汀对Aβ(1-42)诱导AD模型抗凋亡作用的研究.中国老年学杂志,2009,29(5)：551-554
35张晓杰,.牛英才,兴桂华,等.通络救脑口服液对AD大鼠学习记忆能力及AChE表达的影响.中华中医药杂志,2007,22(6)：410-413
36臧艳平,马涤辉.β-七叶皂甙钠对老年性痴呆大鼠模型脑内炎症损伤的保护作用.中国神经免疫学和神经病学杂志,2007,14(4)：194-1961
37 Yamaguchi Y,Kawashima S. Effect of amyloid-β (25-35)on passive avoidance, radia-arm maze learning and choline acetyl-tranferase activity in the rat. Eur J Pharmacol,2001,412:(3):265-272
38 Pavia J.Alberch J, AlvarezI,et al. Repeated intracere broventricular administration of β-amyloid25-35 to rats decreases muscarinic receptors in cerebral cortex. Neurosci Lett,2000,278(122):69-72
39 Duyckaerts C,Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences. Acta Neuropathol,2008,115 (1): 5-38
40 Frautschy SA, Yang F, Irrizarry M, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol.1998,152 (1):307-317
41 Lefterov I.Bookout A, Wang Z, et, al. Expression profiling in APP23 mouse brain:inhibition of Abet a amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener.2007,22 (2)20
42 Lefterov I, Fitz NF, Cronican A, et al. Memory deficits in APP23/Abcal+/-mice correlate with the level of Abeta oligomers. ASN Neuro.2009,30;1 (2)pii:e00006
43 Daumas S.Sandin J, Chen KS,et al.Faster forgetting contributes to impaired spatial memory in the PDAPP mouse:deficit in memory retrieval associated with increased sensitivity to interference? Learn Mem.2008,26; 15(9):625-632
44 Ambree O, Leimer U, Herring A, et, al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice:involvement of multiple pathways. Am J Pathol.2006,169 (2):544-552
45 Fagan AM, Watson M, Parsadanian M, et al. Human and murine ApoE markedly alters A β metabolism before and after plaque formation in a mouse model of Alzheimer' s disease. Neurobiology of Disease,2002,9:305-318
46唐军,徐海伟,周光纪等.阿尔茨海默病转基因小鼠的研究现状与展望.中国行为医学科学,2006,15<2)：190-192
47应春怡,陈系古,陈汝筑等.神经系统退行性疾病相关的Tau蛋白及其转基因动物模型.中华神经医学杂志,2005,4(1)：100-103
48 Lin WL, Lewis J, Yen SH, et al. Filamentous tau in oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation. Am J Pathol.2003,162(1):213-218
49 Ramsden M, Kotilinek L, Forster C, et al. Age-dependent neurofibril ary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci.2005,25(46):10637-10647
50 Leroy K, Bretteville A,Schindowski K,et al. Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice.2007,171(3):976-992
51 Ke YD,Delerue F, Gladbach A, et al. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease.PLoS One.2009,4(11):e7917
52 Das HK. Transcriptional regulation of the presenilin-1 gene:implication in Alzheimer's disease. Front Biosci.2008,13:822-832
53JanusC, Amelio SD, AmitayO, et al. Spatial learning in transgenic mice expressing human presenilinl (PS1) transgenes. Neurobiology of aging.2000,21:541-549
54 Malik B, Currais A, Andres A, et al. Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the presenilin-1 Alzheimer's disease brain. Cell Cycle.2008,7(5):637-646
55 Cedazo-Minguez A.Apolipoprotein E and Alzheimer's disease:molecular mechanisms and therapeutic opportunities.J Cell Mol Med.2007,11(6):1227-38
56 Ezra Y, Oron L, Moskovich L,et al. Apolipoprotein E4 decreases where as apolipoprotein E3 increases the level of secreted amyloid precursor protein after closed head injury. Neuroscience,2003,121:315-325
57李达兵,唐军,范晓棠,等.PS1/APP双转基因AD模型小鼠与Aβ1-40海马注射AD模型大鼠的组织病理学比较.第三军医大学学报,2006,28(16)：1648-1651
58 Ribe EM, Perez M, Puiq B, et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis.2005,20 (3):814-822
59夏春梅,龚琦,傅燕,等.阿尔茨海默病双表达转基因小鼠(hAPP/hACHE)模型的初步建立.实验动物与比较医学,2007,27(2)127-129,136
60 Samura E, Shoji M, Kawarabayashi T, et al. Enhanced accumulation of tau in doubly transgenic mice expressing mutant beta APP and presenilin-1. Brain Res,2006,1094(1):192-199
61 Lewis J,Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science,2001,293 (5534):1487
62 Wirths O, Weis J, Szczygielski J, et al. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease.Acta Neuropathol (Berl),2006,111 (4):312-319
63 Oddo S, Caccamo AKitazawa M, et al. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobigy of Aging.2003,24(8):1063-1070
64 Oddo S, Caccamo A, Jason D, et al. Triplet transgenic Model of Alzheimer's Disease with Plaques and Tangles:Intracellular A β and Synaptic Dysfunction. Neuron(S0896-6273),2003,39:409-421
65 Rhein V, Song X,Wiesner A,et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl:Acad Sci USA.2009,106 (47):20057,-20062
66郑妮,汤宇,黎赛,等：新型复合式老年痴呆小鼠模型的建立.中南药学,2009,7(7)：481-484
67杨晓娟,张生林,陈芸,等.新型复合式老年痴呆动物模型的建立.Chisese journal of integrative medicine of cardio cerebrovascular disease,2006,4 (4):318-320
68曾芳,余曙光,唐勇,等.老年性痴呆复合动物模型研究概况.中国神经免疫学和神经病学杂志,2007,14(4)：197-200
69 Schuster D, Ra jendran A,Hui SW,et al. Protective effect ofcolostrinin on neuroblastoma cell survival is due to reduced aggregation of beta-amyloid. Neuropep tides,2005,39 (4):419-426
70 Nagai Y, Ogasawara A, Heese K. Possiblemechanisms ofAbeta (1-40) orA beta (1-42) induced cell death and their rescue factors. Nippon Yakurigaku Zasshi,2004, 124(3):135
71 Yun SW,Kouznetsova E,Nitschke C, et al. beta-Amyloid deposition and prion infection in adult primary brain cell long-,term culture model. Biochem Biophys Res Commun.2007,360(3):520-524
72张大鹏,陈云波,王奇,等.人参皂苷Rg1对淀粉样β蛋白诱导大鼠海马神经元损伤的保.中国临床康复,2006,10(23)：139-42
73王玉,万海同,严伟民,等.川芎嗪与葛根素合用对海马神经元损伤后的影响.中国中药杂志,2008,33(4)：424-427
74陈勤,李磊珂.远志皂苷对β淀粉样蛋白1-40诱导的体外培养皮层神经细胞损伤的保护作用.中国中药杂志,2007,32(13)：1336-1339
75 Lambert MP, Stevens G, Sabo S, et al. Beta/A4-ecoked degeneration of differentiated SH-SY5Y human neuroblastoma cells. J Neurosci Res,1994,39 (4): 377-385
76沈杰,陈晓春,林旭,张静.SH-SY5Y细胞高表达糖原合成激酶3β对tau蛋白磷酸化和微管稳定性的影响.中国病理生理杂志,2009,25(2)：254-258
77 Hong XJ, Yong J, Yan R, et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid protein in cultured cells. Neurosci Lett,2004, 367:123-128
78 Fang BY, Jia LF, Jia J P. Chinese Presenilinl V97L mutation enhanced A β 42 levels in SH-SY5Y neuroblastoma cells. NeurosciLett,2006,06:33-37
79杨潘,宋秋洁,王月华,等.淫羊藿黄酮对APP695基因转染神经细胞β-淀粉样肽及β-分泌酶的影响.中国康复理论与实践,2009,15(2)：126-128
80邵世滨,丁岩,张亚伦,等.人参皂苷Rgl对Aβ25-35诱导的Alzheimer's病细胞模型作用的研究.中国老年学杂志,2007,27(24)：2378-2381
81王丽娜,夏文,杨玲玲等.开心散对Aβ25-35诱导损伤SH-N-K神经细胞的保护作用及机制.毒理学杂志,2007,21(1)：22-26
82谢朝阳,梅寒芳,祝其锋.p淀粉样肽25-35对PC细胞p53和bc1-2基因表达的影响.广东医学院学报,2005,23(2)：121-123
83黄忠仕,农嵩,谢海渊,等.二苯乙烯苷对Aβ25-35致NG108-15损伤的保护作用.右江医学,2008,36(5)：517-519
84吴蕾,陈云波,王奇,等.人参皂苷对Aβ25-35蛋白诱导的老年性痴呆体外模型NG108-15神经元细胞凋亡的抑制作用.广州中医药大学学报,2007,24(2)：126-131
1魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考.中华中医药杂志,2005.20(8)：496-498
2邓家刚,郝二伟,范丽丽,覃骊兰..中医药对老年性痴呆认识和防治的研究进展.辽宁中医杂志,2007,34(11)：1659-1661
3郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
4邢长伟,张学峰,王景洪.从肾论治老年性痴呆研究进展.陕西中医学院学报,2004,27(1)：72-74
5李敏才,胡振武,肖志宏,补肾益智方对痴呆型大鼠的学习记忆功能影响.临床和实验医学杂志.2006,5(10)：1525
6马世平,詹莹,瞿融.当归芍药散的抗氧化作用研究.中药药理与临床.2001,17(3)：1-3
7高影,李有田,郑学清.益脑通脉汤治疗老年性痴呆症50例疗效观察.中国老年学杂志,2006,26(1)：100-101
8何英,方卓.化痰开窍法在神经系统疾病中的临床应用.辽宁中医药大学学报,2007,9(1)：40-42
9王平,刘玲,石学敏,等.加味温胆汤对SAM-P/10老化痴呆鼠3个脑区兴奋性氨基酸的影响.中国医院药学杂志,2002,22(11)：645-648
10孙明杰,于友华.清热解毒中药防治老年性痴呆症之理论探讨.中国中医基础医学杂志,2003,9(2)：17,24
11张晓杰,牛英才,兴桂华,李澎涛.通络救脑口服液对AD大鼠学习记忆能力及AChE表达的影响.中华中医药杂志,2007,(6)：410-412
12张艺平,韩鹏.黄连解毒汤治疗脑病的药理研究及临床研究新进展.中华实用中西医杂志.2003,16(12)：1832-1834
13刘学源,赵伟康,徐品初,等.调心方对杏仁核注射Aβ25-35诱导的阿尔茨海默病模型大鼠的影响.中草药,2004,35(1)：50-53
14 Auld D S,Kornecook TJ, Bastianetto S, et al. Alzheimer's disease and the basal forebrain cholinergic system:relations to beta-amyloid peptides, cognition,and treatment strategies.Prog Neurobiol.2002,68 (3):209-245
15丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响.中国老年学杂志,2004,24(12)：1183-1185
16谢宁,何秀丽,周妍妍,等.地黄饮子对老年痴呆模型大鼠行为学、AChE及Na+T+-ATP. Ca2+-ATP酶活性的影响.中医药学刊,2004,22(7)：1162-1163
17李玺,张英泽,张智燕,等.脑尔康对Alzheimer病小鼠脑细胞凋亡相关基因表达的影响.中国老年学杂志,2004,24(5)：433-434
18 Wang R, Tang XC. Neuroprotective effects of huperzine a natural cholinesterase inhibitor for the treatment of Alzheimer's disease. Neurosignals.2005,14(1-2): 71-82
18王子玫,孙启祥,刘庆丰,等.ZDY102对痴呆大鼠脑M受体的影响.中国药理学通报,2004,20：997-100
20钟振国,屈振国,王乃平,等.三七总皂苷对Alzheimer's病大鼠模型大脑胆碱能神经病理损害的保护作用.中药材,2005,28(2)：119-122
21 Hongxiao Jia,Yong Jiang,Yan Ruana,et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid-protein incultured cells. Neuroscience Letters,2004,367:123-128
22吴永强,姚文兵,高向东,等.红景天提取物对小鼠记忆获得性障碍的改善作用.中国药科大学学报,2004,35(1)：69-72
23 Manuel Buttini, Eliezer Masliah, Robin Barbour,et al. Beta-Amyloid Immuno-therapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease. The Journal of Neuroscience.2005,25 (40):9096-9101
24王春艳,郭景森,田晶,崔万丽.β淀粉样蛋白与阿尔茨海默病.吉林医药学院学报,2009,30(2)：99-102
25余锐,肖飞,李晓光,等.去痴灵脂溶性提取物血清抑制M146L细胞分泌β淀粉样蛋白.中国新药杂志,2006,15(13)：1061-1063
26张婷,董克礼.益智健脑颗粒对阿尔茨海默病患者脑脊液β淀粉样蛋白含量的影响.中国老年学杂志,2007,27(6)：1080-1081
27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.中国老年学杂志,2006,26(7)：924-926
28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淀粉样蛋白及前体蛋白的影响.北京中医药大学学报,2009,32(8)：553-556
29周忠光,韩玉生,姜国华.补气活血方对多因素损伤AD大鼠血清β淀粉样蛋白细胞因子的影响.中医药学报,2007,35(2)：16-18
30熊平,蒋灵芝,黄兆胜.补肾活血化痰中药复方对D-半乳糖诱发衰老模型大鼠中枢神经递质及β-淀粉样蛋白的影响.中国实验方剂学杂志,2007,13(2)：42-45
31江励华,段金廒,王明艳,等.华佗健聪汤药物血清对Aβ所致神经元损伤保护作用的实验研究.中国中医药科技,2009,16(1)：46-48
32朱未名,胡海燕.清心开窍方对 年痴呆小鼠脑自由基代谢及海马CA1区神经细胞形态的影响.中国实验方剂学杂志,2007,13(10)：57-60
32谢宁,宋琳,牛英才,等.加减地黄饮子对Aβ1-40所致AD大鼠学习记忆及抗氧化作用的影响.中医药学刊,2005,23(2)：212-214
33 Egashira N, Iwasaki K,Akiyoshi Y, et al. Protective effect of Toki-shakuyaku-san on amyloid beta25-35 induced neuronal damage in cultured rat cortical neurons. Phytother. Res,2005,19 (5):450-453
34周永其,邓湘平,顾振纶.石杉碱甲对氧自由基的影响.中国野生植物资源,2004,23(2)：44-45
35黄可儿,柯雪红,陈为,等.醒神液对老年性痴呆大鼠模型脑内神经递质的影响.中国老年学杂志,2003,23(11)：775-776
36罗喜荣,李红艳,郝小燕.天参益智方对老年性痴呆模型大鼠中枢神经递质的影响.中药药理与临床,2007,23(1)：65-67
37 Heneka MT,O' Banion MK. Inflammatory processes in Alzheimer's disease. Neuroimmunol,2007,184 (122):69-91
38 Vasto S, Candore G, Listi F, et al. Inflammation, genes and zinc in Alzheimer's disease. Brain Res Rev,2008,58 (1):96-105
39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.药药理与临床,2006,22(2)：48-49
40宋琳,安平,‘朴钟源,等.地黄饮子对老年性痴呆模型大鼠的学习记忆及炎性反应的影响.时珍国医国药,200718(7)：1654-1656
41林丽莉,宋秋洁,叶翠飞,等.淫羊藿黄酮对阿尔茨海默病模型神经炎性反应的影响.中国康复理论与实践,2009,15(2)：123-125
42孟燕,王蓉,刘梦霞,盛树力.阿尔茨海默病患者脑神经元调亡机制中的相关因素研究.中华老年医学杂志,2006,25(4)：245-247
43王珏,林胜友.中药抑制细胞凋亡的研究进展.云南中医中药杂志,2007,28(11)：46-48
44钱云飞,姚文兵,王华,等.开心散抑制过氧化氢诱导的PCI2细胞凋亡的机制.中国天然药物,2007,9(5)：379-384
45谢宁,邹纯朴,牛英才,等.地黄饮子对海马神经SAD模型细胞凋亡的调控作用.中国实验方剂学杂志,2004,10(4)：29-33
46谢宁,宋琳,姚丽芬,等.地黄饮子对阿尔茨海默病模型鼠脑神经元细胞凋亡及超微结构的影响.中国临床康复,2005,9(37)：93-95
47何明大,刘运林.脑灵汤对阿尔茨海默病模型鼠凋亡调控基因的影响.中国现代医学杂志,2005,15(22)：3398-3041
48胡亚萍,王平,胡永年,等.加味温胆汤含药脑脊液抗Aβ细胞毒性作用及其机制的实验研究.中国实验方剂学杂志,2007,13(7)：26-28
49谢桂琴,陈启盛.老年性痴呆的中药治疗现状.中国老年学杂志,2002,22(5)：4192-4211
50周爱玲,茅家慧,朱燕.药复方脑益康干预阿尔茨海默病模型小鼠脑组织神经生长因子及脑源性神经营养因子mRNA的表达.中国临床康复,2006,10(31)：16-18
51丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响.中国老年学杂志,2004,24(12)：1183-1185
52黄理钧,龚俊华,梁烨,等.益智健脑颗粒对AD模型大鼠学习记忆能力及海马神经元BDNF表达的影响.中国行为医学科学,2006,15(9)：780-783
53楚晋,叶翠飞,李林,等.二苯乙烯苷对D-半乳糖致脑老化小鼠学习记忆及神经营养因子的影响.中国药房,2005,16(1)：13-16
54张保平,刘畅,姜秀云.补肾活血化痰法对血管性痴呆大鼠单胺氧化酶及单胺类神经递质的影响.中西医结合心脑血管病杂志,2006,4(8)：94-695
55 Gao Guo-li,Che Guang-sheng, jiangyuan,et al. Effect of compound total extract ginseng and tall gastrodia tuber on content of monoamine transmitters in brain tissue of rats with vascular dementia. Chinese Journal of Clinical Rehabilitation.2006,10(19):182-183,186
56丛伟红,刘建勋,徐立,秦川.人参、银杏叶提取物对PDAPPV717I转基因小鼠海马乙酰胆碱和单胺类神经递质水平的影响.中国中西医结合杂志,2007,27(9)：810-813
57陈建宗,黄晨,高建苑,等.银杏叶提取物对老龄大鼠学习、记忆及有关神经递质的影响.成都中医药大学学报,2004,27(3)：27-28
58 Koo BS, Kwon TS, Kim CH. Salviae miltiorrhizae radix inhibits superoxide generation by activated rat microglias and mimics theaction of amphetamine on in vitro rat striatal dopamine release. Neurochem Res,2004,29(10):1837-1845
60吴尚霖,卞慧敏.酸枣仁油对小鼠学习记忆的影响.中草药,2001,32(3)：246-247
61郭蓉,曹云鹏.雌激素在阿尔茨海默病中的作用研究进展.国外医学.老年医学分册,2007,28(3)：97-100
62姜小帆,曾进.中医药防治阿尔茨海默病的实验研究思路及进展.现代中医药,2006,26(1)：58-60
63方芳,黄敏丽,陈行,等.雌激素对雌性去势大鼠脑组织抗氧化能力的影响.复旦学报(医学版),2004,31(1)：59-62
64周伟勤,邓景岳,毕明刚,杜冠华.淫羊藿苷改善快速老化小鼠SAMP8学习记忆多能及与血清雌激素水平相关性研究.中国实验方剂学杂志,2009,15(9)：38-41
65 Gong CX, Liu F, Grundke-IqbalI,et al.Post translational modifications of tau protein in Alzheimer's disease. JNeural Transm,2005,112 (6):813-838
66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.苏州大学学报(医学版)2009,29(3)：426-429
67 Chauhan NB. Effect of aged garlic extract on APP processing and tauphospho-rylation in Alzheimer's transgenic model Tg2576.J Ethnopharmacol,2006,108: 385-394.
68杨仙凌.治疗老年性痴呆的中药研究进展.浙江中医药大学学报,2007,31(1)：138-140
69王珍.中药抗阿尔茨海默病实验研究进展.现代中西医结合杂志,2008,17(17)：2743-2745
70邓家刚,郝二伟,郭宏伟,柳俊辉.老年性痴呆复方用药规律探讨.山东中医杂志,2007,26(6)：363-364
71周鲁,张卫华,曾令航,贾波.老年性痴呆的复方用药规律研究.辽宁中医杂志,2005,32(3)：243-244
1 Blennow K, de LeonM J,Zetterberg H. Alzheimer's disease. Lancet.2006,368 (9533):387-403
2尹宗宁.中医药防治老年痴呆症的研究进展.中国老年学杂志,2005,25(3)：3545-356
3李慧.中医中药对阿尔茨海默病的干预作用.中国中药杂志,2008,33(21)：2449-2453
4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.中国康复理论与实践,2005,11(5)：324-326
5秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
6陈春富,郎森阳,徐云燕,等.脱氢表雄酮对衰老大鼠体质量和学习记忆的影响.中国临床康复,2006,10(1)：77-79
7王跃春,王子栋,孙黎明,等.动物学习记忆能力的Y-型迷宫测试法.暨南大学学报(自然科学版),2001,22(5)：137-140
8薛承景,李建民.学习和记忆研究的行为学方法论述.河北医药,2007,29(1)：77-78
9秦川,朱华,常洋,高虹.阿尔茨海默症转基因小鼠的初步行为学评价.上海实验动物科学,2000,20(4)：210-212
10杜怡峰,王蓉,姬志娟,盛树力.APP17肽对APP转基因小鼠：学习记忆能力和海马神经细胞凋亡的影响.中国神经免疫学和神经病学杂志,2007,14(1)：7-10
11楚晋,李林,叶翠飞,等.淫羊藿黄酮对APP转基因小鼠学习记忆及β-amyloid生成的影响.中国科学技术大学学报,2008,38(4)339-448
12张兰,邢颖,赵玲,等.不同时程APP转基因小鼠学习记忆改变及参乌胶囊、二苯乙烯苷。的干预作用.中国行为医学科学,2006,15(3)：193-196
13 Dewachter I, Van Dorpe J, Smeijers L, et al. Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilinl. Journal of Neuroscience,2000,20 (17):6452-6458
14 Buckaer RL. Memory and executive function in aging and AD:multiple factors that cause decline and reserve factors that compensate. Neuron,2004,44 (1): 195-208
15朱庄庄,刘昌敏,冯丽.中医药治疗老年痴呆症的研究进展.中国临床康复,2004,18(13)：2598-2600
16邓家刚,郝二伟,范丽丽,覃骊兰.中医药对老年性痴呆认识和防治的研究进展.辽宁中医杂志,2007,34(11)：1659-1661
1 Tanzi RE, Bertram L. Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective. Cell,2005,120(4):545:555-1063
2 Thinakaran G, Koo EH. Amyloid Precursor Protein Trafficking, Processing, and Function. J Biol Chem.2008 October31,283 (44):29615-29619
3 Forman MS, Trojanowski JQ,Lee VM, et al. Neurodegenerative diseases:A decade of discoverie spaves the way for therapeutic breakthroughs. NatMed,2004,10: 1055-1063
4田金洲,徐意,时晶.中药干预β淀粉样肽生成、代谢及其毒性作用的研究概况.中国老年学杂志,2006,26(4)：557-560
45袁彪,叶冰,董青青,黄国钧.老年性痴呆动物模型的研究进展.实验动物科学,2009,26(1)：45-48
6 Duyckaerts C, Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences. Acta Neuropathol,2008,115 (1):5-38
7 Hooper NM. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prionprotein. Biochem Soc Trans,2005,33:335-338
8 Fukumoto H, Cheung BS, Hyman BT, et al. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol,2002,59:1367-1368
9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.上海实验动物科学,2000,20(4)：210-212
10秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
11 Tang X, Milyavsky M, Goldfinger N, Rotter V. Amyloid beta precursor like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress. Oncogene,2007,26(52):7302-7312
12Masliah E, Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer' s disease. J Alzheimers Dis,2006,9 (Supp13):91-99
13 Thinakaran G,Koo EH.Amyloid Precursor Protein Trafficking, Processing, and Function. J Biol Chem.2008 October31,283 (44):29615-29619
14 Wu Y, Ji SR,Jiang WL, et al. Comparison of the aggregation of beta-amyloid peptidel-42 and beta-amyloid peptidel-40. J Chin ElectrMicroscopy Soc,2003, 22:212-251
15 Wirths 0, Multhaup G, Bayer et al.A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide:the first step of a fatal cascade.J Neurochem,2004,91:513-520
16 Luo Y. BACE(Beta-secretase) knockout mice do not acquire compensatory gene expression changes ordevelop neural lesions over time.Neurobiol Dis 2003, 14:81-88
17 Richardson JC,Kendal CE,Anderson R.Ultrastructural and behavioral changes precede amyloid deposition in a transgenic model of Alzheimer's disease. Neurosci,2003,122:213-228
18 Squire LR,Zola SM. Structure and function of declarative and nondeclarative memory systems. ProcNatlAcad Sci USA,1996,93(24):13515-1352
19 Oddo S, Caccamo A, Tseng B, et al. Blocking Abeta42 accumulation delays the onset and progression of tau pathologyvia the C terminus of heat shock protein70-interacting protein:a mechanistic link between Abeta and tau pathology. JNeurosci,2008,28(47):12163-12175
20 Georganopoulou DG. Nanoparticle based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease.Proc Natl Acad Sci USA,2005,102:2273-2276
21俞建洪,尹其华,刘慧英,等.血清、脑脊液Tau蛋白与β-淀粉样蛋白浓度在早期AD、VD患者的对照研究.心脑血管病防治,2009,9(2)：128-130
22张雪玲,丁新生,程虹,等.脑脊液中Aβ检测对老年期痴呆早期诊断的意义.现代中西医结合杂志,2003,12(8)：789-792
23 Lewczuk P, Esselmann H,OttoM,et al.Neurochemical diagnosis of Alzheimer's dementia by CSF Abeta42, Abete42/Abeta40 ratio and total tau. Neurobiol Aging,2004,25(3):273-281。
24 Strozyk D, Blennow K, White LR, et al.CSF Abeta42 levels correlate with amyloid neuropathology in a population based autopsy study. Neurology,2003,60(4): 652-656
25 Fagan AM,Mintun MA,Mach RH,et al.Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol,2006,59 (3): 512-519
1秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
2 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356
3张癸荣,高登莲,殷明.Aβ的神经毒性与阿尔茨海默病的研究进展.解放军药学学报,2004,20(1)：58-61
4郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
5 Sgourakis NG, Yan Y,McCallum SA,et al.The Alzheimer's peptides A β 40 and 42 adopt distinct conformations in water:a combined MD/NMR study. J Mol Biol.2007, 368 (5):1448-1457
6 Lacor PN, Buniel MC, Furlow PW, et al.Abeta oligomer-induced aberrations in synapse composite on, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci.2007,27 (4):796-807
7Wahlstrom A, Hugonin L,Peralvarez-Marin A, et al. Secondary structure conversions of Alzheimer's Abeta(1-40) peptide induced by membrane mimicking detergents. FEBS J,2008,275 (20):5117-5128
8 Bresler T, Shapira M, Boeckers T, et al. Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly. J Neurosci,2004, 24(6):1507-1520
9 Bourne JN, Harris KM. Balancing structure and function athippocampal dendritic spines. Annu RevNeurosci,2008,31:47-67
10 Yoshiike Y,Mina i R,Matsuo Y, et al.Amyloid oligomer conformation in a group of natively folded proteins. PLoS One,2008,3(9):e3235
11 Deshpande A, Mina E, Glabe C, et al.Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci.2006,26 (22):6011-6018
12 Coleman P,Federoff H, Kurlan R. A focus on the synapse forneuro protection in Alzheimer disease and other dementias. Neurology,2004,63:1155-1162
13张雷明,田金洲,尹军祥,等.中药复方金思维对APPV717 I转基因小鼠海马神经损伤的保护作用.中草药,2009,40(3)：410-415
14 Henze DA, McMahond BT, Harris KM, et al. Giant miniature EPSCs at the hippocampal mossy fiber to CA3 pyramidal cell synapse are monoquantal.J Neurophysiol,2002, 87:15-29:
15 Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer's disease. Prog Neurop Sychophaimacol BiolPsychiatry,2005,29:407-101
16 Manczak M, Anekonda TS, Henson E, et al. Mitochondria are a direct site of A β accumulation in Alzheimer's disease neurons:implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics, 2006,15(9):1437-1449
17辛颖.线粒体与神经退行性病变.医学综述,2008,14(4)：.520-521
18 Takahashi RH, Almeida CG, Kearney PF,et al. Oligomerization of Alzheimer's β-amyloid within processes and synapses of cultured neurons and brain. J of Neurosci,2004,24(14):3592-3599
19 LaFerla FM, Green KN,Oddo S.Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci,2007,8(7):499-509
20 Cook DG, FormanMS,Sung JC, et al. Alzheimer's A beta (1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. NatMed, 1997,3(9):1021-1031
21Vieira HL, Belzacq AS,Haouzi D,et al.The adenine nucleotide translocator:a target of nitric oxide,peroxynitrite,and 4-hydroxynonenal, Oncogene,2001, 20(32):4305-4316
22 Lustbader JW,Cirilli M, Lin C, et al.ABAD directly links A β to mitochondrial toxicity in Alzheimer's disease. Science,2004,304 (1):448-452
23 Lustbader JW, CirilliM,Lin C, et al.ABAD directly links to mitochondrial toxicity in Alzheimer's disease. Science,2004; 304 (5669):448-452
24 Casley C S, Land J M,Sharpe MA,et al. β-amyloid fragment25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis,2002, 10(3):258-267
25葛振英,石纯,许晓伍,等.雌激素撤退大鼠海马和基底前脑神经元线粒体超微结构学观察.解剖学研究,2006,28(2)131-133
26 Hirai K.Aliev G, Nunomura A,et al. Mitochondrial abnormalities in Alzheimer' s disease. J Neurosci.2001,21(9):3017-3023
27 Zhu X, Smith MA, Perry G, et al. Mitochondrial failures in Alzheimer's disease. AmJ Alzheimers Dis Other Demen,2004,19 (6):345-352
28 Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications. Ann Neurol,2005; 57 (5):695-703
29 Sullivan PG,Brown MR. Mitochondrial aging and dysfunction in Alzheimer's disease. Prog Neurop Sychophaimacol BiolPsychiatry,2005; 29:407-410
30 Blass J P. Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res.2001,66(5):851-856
31 Mattson MP. Pathways towards and away fromAlzheimer's disease. Nature,2004, 430(7000):631-639
32 Cardoso SM, Santana I.SwerdLow RH, et al. Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity. J Neurochem,2004,89(6): 1417-1426
31Kanaan NM, Kordower JH, Collier TJ. Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamineneurons:relevance to selective neuronal vulnerability.J CompNeurol,2007,10; 502 (5):683-700
33 Castejon OJ. Lysosome abnormalities and lipofucsin content of nervecells of edematous human cerebral cortex. J Submicrosc CytolPathol,2004,36 (3-4):263-271
34 Petersen RC, Negash S. Mild cognitive impairment:an overview. CNS Spectr,2008, 13(1):45-53
35朱轶冰,陆佩华,盛祖杭.AD发病机制的新探索：轴浆运输障碍假说.生理科学进展,2008,39_(1)：5-9
36崔德芝,张恭新,朱振铎.老年性痴呆的中医理论探讨.山东中医杂志：2006,25(10)：655-657
37黄亮,黄燕.血脑屏障功能的中医药研究现状.中医药学刊,2005,23(9)：1648-1650
1 Pereira C,Ferreiro E, Cardoso SM,et al.Cell degeneration induced by amyloid-beta peptides:Implications for Alzheimer's disease. J Mol Neurosci, 2004,23(1-2):97-104
2 Kawasumi M, Hashimoto Y,Chiba T,et al. Molecular mechanisms for neuronal cell death by Alzheimer's amyloid precursor protein-relevant insults. Neurosignals, 2002:236-250
3吕良,钟振国.阿尔茨海默病淀粉样β蛋白诱导神经元凋亡的研究进展.中西医结合心脑血管病杂志,2007,5(6)：517-519
4朱汉华,李浪,汪熠,等.TUNEL检测心肌细胞凋亡的影响因素探讨.广西医科大学学报,2009,26(1)：24-26
5 Zhu Y, Xu J, Kwong WH, et al. Microscopic analysis of the different regions of three Alzheimer brains aged 93,94, and 104 years old (J). Int.J Neurosci.2007, 117(10):1403-1413
6 Affar EB, Germain M, Winstall E, et al. Caspase3 mediated processing of poly (ADP-ribose) glycohydrolase during apoptosis.J BiolChem,2001,276 (4): 2935-2942
7 Boatright KM, Salvesev GS.Mechanisms of caspase activation. Curr Opin Cell Biol,2003,15(6):725-731
8 Eckert A, Marques CA, Keil U. Increased apoptotic cell death in sporadic and genetic Alzheimer's disease. Ann N Y Acad Sci.2003,1010:604-609.
9胡胜全,余惠,刘塔斯,杨大坚.人参水提物对β淀粉样蛋白诱导SH-SY5Y细胞凋亡的保护作用.时珍国医国药,2009,.20(2)：257-259
10苏心,张文治.β-淀粉样蛋白致胚胎鼠大脑神经干细胞凋亡作用的研究,中国现代神经疾病杂志,2005,5(4)：248-251
11杨戈,林水淼,赵伟,等.调心方有效部位对类AD大鼠脑组织凋亡信号转导分子Caspase-3及凋亡相关基因bc 1-2、 baxmRNA表达的影响.中国中西医结合杂志,200626(2):147-151
12 BehlC, Moosmann B. Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds. Biol Chem,2002,383(3-4):521-536
13 Francois GG,Daigen X,George S, et al.Involvement of caspases Inproteolytic cleavage of Alzheimer's amloid-precursor protein and amyloidogenic A β peptide formation. Cell,1999,97(4):395-406
14叶静,刘协和,邓红,等.β-淀粉样多肽诱导神经元凋亡和Caspase-3蛋白表达的实验研究.中国中西医结合杂志,2006,26(2)：147-151
15庄莹,陈杰.阿尔茨海默病病因及发病机制研究进展.吉林医药学院学报,2008,29(4)：101-104
16李龙宣,许志恩,赵斌,等.Alzheimer病患者脑脊液中炎前和抗炎细胞因子以及凋亡信号分子的变化.中国神经免疫学和神经病学杂志,2005,12(4)：212-215
17宋建德,袁丽萍,梁勇,等.药用植物多糖的免疫作用研究进展.中兽医医药杂志,2004,2：22-24
18李刚,曾祥发,陆晖,李芳.石菖蒲健脑益智作用的研究进展.广西中医学院学报,2009,12(1)：74-76
1 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356
2 Yanker BA, Duffy L K, Kirschner DA. Neurotrophicand neurotoxic effects of amyloid protein:reversal by tachykinin neuroprptide. Science,1990,250 (4978):279-282
3钱亦华,史利利,杨杰,等.原代培养小鼠皮层神经细胞对淀粉样蛋白的内化作用.中南大学学报(医学版),2008,33(11)：1019-1027
4 Schuster D, Rajendran A, Hui SW, et al. Protective effect ofolostrinin on neuroblastoma cell survival is due to reduced aggregation of beta amyloid. Neuropep tides,2005,39 (4):419-426
5 Nagai Y, Ogasawara A,Heese K.Possible mechanisms of A beta(1-40) or A beta (1-42)-induced cell death and their rescue factors. Nippon Yakurigaku Zasshi,2004,124(3):135-143
4魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考.中华中医药杂志,2005,20(8)：496-498
6郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
7吴庆四,徐东芳,刘冬梅,等.糖皮质激素促β-淀粉样蛋白致海马神经元损伤.中国神经精神疾病杂志,2008,34(3)：178-180
8 Tomohiro Chiba, Marina Yamada, Yuichi Hashimoto, et al. Development of a femtomolar acting human in derivative named colivel in by attaching activity dependent neurotrophic factor to its N terminus:characterization of colivelin mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo. The Journal of Neuroscience,2005,25(44):10252-10261
9邵世滨,丁岩,张亚伦,等.人参皂苷Rgl对Aβ25-35诱导的Alzheimer's病细胞模型作用的研究.中国老年学杂志,2007,27(24)：2378-2381
10王玉,万海同,严伟民,等.川芎嗪与葛根素合用对海马神经元损伤后的影响.中国中药杂志,2008,33(4)：424-427
11张魁华,赖世隆,胡镜清,等.补肾益智方对AD细胞模型钙离子内流、细胞骨架、细胞凋亡的影响.中国中医基础医学杂志,2002,8(7)：23-25
12 Hashimoto M, Rockenstein E, Crews L, et al.Role of protein aggregationin mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson' s diseases. Neuromol Med,2003,4:21-36
13聂晶,罗勇,石京山.淫羊藿苷对Aβ25-35所致神经细胞损伤的保护作用研究.遵义医学院学报,2007,30(3)：229-231,235
2 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science.2002,297 (5580):353-356
3 Murphy MP,LeVine H 3rd. Alzheimer's Disease and the β-Amyloid Peptide. J Alzheimers Dis.2010,19 (1):311-23
4 E.Mohandas, V. Ra jmohan, B. Raghunath. Neurobiology of Alzheimer's disease. Indian J Psychiatry.2009,51 (1):55-61
5 Qi-Takahara Y,Morishima-Kawashima M, Tanimura Y, et al. Longer forms of amyloid beta protein:implications for the mechanism of intramembrane cleavage by gamma-secretase. The Journal of Neuroscience,2005,25 (2):436-445
6 Thinakaran G,Koo EH. Amyloid Precursor Protein Trafficking, Processing,and Function. J Biol Chem.2008 October31,283 (44):29615-29619
7 Zheng H, Koo EH. The amyloid precursor protein:beyond amyloid. Mol Neurodegener. 2006, Jul3; 1:5
8 Kim J,Onstead L, Randle S, et al.Abeta40 inhibits amyloid deposition in vivo. J Neurosci,2007,27:627-633
9 Luhrs T, Ritter C, Adrian M, et al.3D structure of Alzheimer's amyloid beta (1-42) fibrils. Proc Natl Acad Sci USA,2005, Nov 29,102 (48):17342-17347
10 Sgourakis NG, Yan Y.McCallum SA, et al.The Alzheimer's peptidesA β 40 and 42 adopt distinct conformations in water:a combinedMD/NMR study. J Mol Biol.2007, 368:1448-1457
11 Petkova AT, Leapman RD,Guo Z, et al. Self-propagating, molecularlevel polymorphism in Alzheimer's β-amyloid fibrils. Science,2005,307:262-265
12 Chiti F, Dobson CM. Protein misfolding, functional amyloid,and human disease. Annu Rev Biochem.2006,75:333-366
13 Sgourakis NG, Yan Y,McCallum SA,et al.The Alzheimer's peptides A P 40 and 42 adopt distinct conformations in water:a combined MD/NMR study. J Mol Biol.2007, 368(5):1448-1457
14 Gong Y, Chang L, Viola KL, Lacor PN, et al. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A.2003 Sep2; 100(18):10417-10422
15 Malito E,Hulse RE,Tang WJ. Amyloid beta-degrading cryptidases:insulin degrading enzyme, presequence peptidase, and neprilysin.Cell Mol Life Sci.2008 Aug;65(16):2574-2585
16 El-Amouri SS, Zhu H, Y,u J,Marr R, et al. Neprilysin:an enzyme candidate to slow the progression of Alzheimer's disease. Am J Pathol.2008 May; 172(5):1342-1354
17 Caccamo A, Oddo S, Sugarman MC,et al.Age and region dependent alterations in Abeta degrading enzymes:implications for Abeta induced disorders. Neurobiol Aging.2005,26 (5):645-654
18 Marr R A, Guan H, Rochenstein E, et al. Neprilysin Regulates amyloid Beta peptide levels. Journal of Molecular Neuroscience,2004,22 (1-2):5-11
19 de Tullio MB, Morelli L, Castano EM. The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme:a biological perspective. Prion.2008,2(2):51-56
20 Miller BC, Eckman EA, Sambamurti K, et al. Amyloid2beta peptide levels in brain are inversely correlated with insulysin activitylevels in vivo. Proc NatlAcad SciUSA,2003,100 (10):6221-6226
21 FarrisW,Mansourian S,Leissring MA, et al. Partial loss of function mutations in insulin degrading enzyme that induce diabetes aloimpair degradation of amyloid beta-protein. Am J Pathol,2004,164(4):1425-1434
22 Wang DS, Dickson DW,Malter JS. β-Amyloid Degradation and Alzheimer's Disease. Biomed Biotechnol.2006, (3):58406-58413
23 Jacobsen JS,Comery TA,Martone RL, et al. Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.Proc Natl Acad Sci USA.2008, 105(25):8754-8759
24 Yang YH, Liu CK. Angiotensin-converting enzyme gene in Alzheimer's disease. Tohoku J Exp Med.2008,215 (4):295-298
25 Hemming ML,Selkoe DJ,Farris W. Effects of prolonged angiotensin converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse'of Alzheimer disease. Neurobiol Dis.2007,26 (1):273-281
26 Jeynes B,Provias J.Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis.Curr Alzheimer Res.2008,5 (5):432-437
27 Judy A Cam, Guojun Bu. Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.Mol Neurodegener, 2006,1:8
28 Bu G, Cam J, Zerbinatti C. LRP in amyloid-beta production and metabolism. Ann N Y Acad Sci.2006,1086:35-53
29 Hert J. LRP:a bright beacon at the blood-brain barrier. J Glin Invest,2003, 112(10):1483-1485
30 Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzhermer's amyloid β-40 peptide from brain by LDL receptor related protein-1 at the blood brain barrier. J Clin Invest,2000,106(12):1489-1499
31 Laura B, Jaeger, Shinya Dohgu, et al.Testing the Neurovascular Hypothesis of Alzheimer's Disease:LRP-1 Antisense Reduces Blood-Brain Barrier Clearance, Increases Brain Levels of Amyloid-β Protein,and Impairs Cognition. Alzheimers Dis.2009 Jul; 17(3):553-70
32 Lue LF, Walker DG,Jacobson S, Sabbagh M. Receptor for advanced glycation end products:its role in Alzheimer's disease and other neurological diseases. Future Neurol.2009,4(2):167-177
33 Miller MC, Tavares R, Johanson CE,et al. Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease.Brain Res.2008,1230:273-280
34 Deane R,Du Yan S, Submamaryan RK,et al.RAGE mediates amyloid β peptide transport across the blood rain barrier and accumulation in brain. Nature.2003, 9(7):907-913
35 Zlokovic BV. New therapeutic targets in the neurovascular pathway in Alzheimer' s disease. Neurotherapeutics.2008,5 (3):409-414.
36 Lam FC,Liu R,Lu P,et al. beta-Amyloid efflux mediated by p-glycoprotein.J Neurochem,2001,76(4):1121-1128
37 Hartz AM,Miller DS,Bauer B. Restoring Blood-Brain Barrier P-glycoprotein Reduces Brain A{beta} in a Mouse Model of Alzheimer's Disease. Mol Pharmacol. 2010. [Epub ahead of print]
38 Hickman SE, Allison EK,El Khoury J.Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008,28(33):8354-8360
40 Murphy MP,LeVine H 3rd. Alzheimer's Disease and the β-Amyloid Peptide.J Alzheimers Dis.2010,19(1):311-323
41 Pearson HA, Peers C. Physiological roles for amyloid beta peptides. J Physiol. 2006,575(Pt1):5-10
42 Plant LD,Webster NJ,Boyle JP,et al.Amyloid beta peptide as a physiological modulator of neuronal 'A' -type- K+ current.Neurobiol Aging,2006,27 (11):1673-1683
4.3 Kamenetz F, Iomita T, Hsieh H, et al. APP processingand synaptic function. Neuron. 2003,37(6):925-937
44 Plant LD, Boyle JP, Smith IF,et al.The production of amyloid beta peptide is a critical requirement for the viability of central neurons.J Neurosci.2003, 23(13):5531-5535
45 Kayed R, Head E, Thompson JI, et al. Common structure of soluble amyloid oligomrrs implies common mechanism of pathogenesis. Science.2003,300:486-489
46 Walsh DM, Klyubin I,Fadeeva JV,et al.Naturally secreted olignmers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002,416(6880):535-539
47 Pike CJ,Cummings BJ, Cotman CW. beta-Amyloid induces neuritic dystrophy in vitro:similarities with Alzheimer pathology. Neuroreport.1992,3(9):769-772
48 Clifford PM, Zarrabi S,Siu G, et al.Abeta peptides can enter the brainthrough a defective blood-brain barrier and bind selectively to neurons. Brain Res,2007, 1142:223-236
49 Resende R,Pereira C, Agostinho P, et al. Susceptibility of hippocampalneurons to Abeta peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res.2007,1143:211-217
50 Akiyana H,Barger S, Barnum S, et al. Inflammation and Alzheimer's diseas. Neurobiol Aging.2000,21 (3):383-421
51 Walker DG, Link J, Lue L F, et al. Gene expression changes by amyloid beta peptide stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. Journal of Leukocyte Biology.2006,79(3):596-610
52 Giovannini MG, Scali C, Prosperi C, et al. Beta-amyloid induced in flammation and cholinergic hypofunction in the rat brain in vivo:in volvement of the p38 MAPK pathway. Neurobiol Dis,2002,11 (2):257-262
53 Hull M, Muksch B, Akundi RS, et al. Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostagland in E-2 release in primary midbrain astrocytes. Neurochemistry International,2006, 48 (8):663-672
54 Ho L, Qin WP,Stet ka BS, et al. Is there a future for cyclo-oxygenase inhibitors in Alzheimer's disease? CNS Drugs.2006,20(2):85-98
55 Tobinick E, Gross H,Weinberger A, et al.TNF-alpha modulation-for treatment of Alzheimer's disease:a 6-month pilot study. Med GenMed.2006,8(2):25
56 Varvel NH,Bhaskar K,Kounnas MZ,et,al. NSAIDs prevent,but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. 2009,119 (12): 3692-702
57 Simard AR,Soulet D,Gowing G,et al.Bone marrow derived microglia p lay a critical role in restricting senile p laque formation in Alzheimerps disease. Neuron.2006,49 (4):489-502
58 Floden AM, Combs CK. Beta amyloid stimulatesmurine postnataland adult microglia cultures in a unique manner. Neurosci,2006,26(17):4644-4648
59 Feiqi Zhu,Caiyun Qian. Berberine chloride increases the activation of microglia by inhibiting the expression of peroxisome proliferator activated receptor gamma in the rat model of Alzheimer's disease. Eur J Neurol, BMC Neurosci,2006,7:78
60 Wyss Coray T,Mucke L. Inflammation in neurodegenerative diseasea double-edged sword. Neuron,2002,35 (3):419-432
61 arnham KJ,Cappai R, Beyreuther K, et al. Delineating common molecular mechanisms in Alzheimer's and prion diseases. TrendsBiochem Sci,2006,31(8): 465-472
62 Sultana R, Perluigi M, Butterfield DA. Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impairment and animal models of AD:role of A-beta in pathogenesis.Acta Neuropathol.2009,118(1):131-150
63 Zilka N, Novak M. The tangled story of Alois Alzheimer. Bratisl Lek Listy,2006,107(9-10):343-345
64 Tanzi RE, Bertram, L. Twenty years of the Alzheime's disease amyloid hypothesis: a genetic perspective. Cell.2005,120(4):545-555
65 De Felice FG, Velasco PT, Lambert MP, et al.A β oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem,2007,282 (15): 11590-11601
66 Hossain S, Grande M, Ahmadkhanov G,et al. Binding of the Alzheimer amyloid beta-peptide to neuronal cell membranes by fluorescence correlation spectroscopy. Exp Mol Pathol,2007,82:169-174
67 Hashimoto M, Rockenstein E, Crews L, et al.Role of protein aggregationin mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromol Med,2003,4:21-36
68 Wallace MN,Geddes JG,Farquhar DA,et al. Nitric oxide synthase inreactive astrocytes adjacent to β-amyloid plaques. Exp Neurol,1997,144:266-272
69 ZHAO Lin, HE Miao,.JIN Wan-bao, et al:Vitamin E administration improves learning and memory deficits in modeling Alzheimer's disease. Chinese Journal of Clinical Pharmacology and Therapeutics.2009,14(1):25-31
70 Reix S,Mechawar N,Susin SA,et al. Expression of cortical and hippocampal apoptosis-inducing factor (AIF) in aging and Alzheimer's disease. Neurobiol Aging.2007,28(3):351-356
71 Patel JR, Brewer GJ.Age-related differences in NFkappaB translocation and Bcl-2/Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons.Exp Neurol.2008,213(1):93-100
72 Louneva N, Cohen JW,Han LY,et al.Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. Am J Pathol.2008,173 (5): 1488-1495
73 Raynaud F,Marcilhac A. Implication of calpain in neuronal apoptosis A possible regulation of Alzheimer's disease. Febs Journal.2006,273(15):3437-3443
74 Starr JM,Armitage P,Armitage P,et al. Blood-brain barrier permeability in Alzheimer's disease:a case-control MRI study. Psychiatry Res.2009,171 (3): 232-241
75 Petersen RC, Negash S. Mild cognitive impairment:an overview. CNS Spectr.2008, 13(1):45-53
76 Yu Yan, Zhou Liang,Xu Feng, et al.Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Nervous Diseases and Mental Health.2008, 8(6):411-413
77 Lustbader JW,Cirilli M, Lin C, et al. ABAD directly links A β to mitochondrial toxicity in Alzheimer's disease. Science.2004,304 (5669):448-452
78 Deshpande A,Mina E, Glabe C,et al. Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons.J Neurosci.2006,26 (22):6011-6018.
79 Lacor PN, Buniel MC, Furlow PW, et al.Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecularbasis for loss of connectivity in Alzheimer's disease. J Neurosci,2007,27 (4):796-807
80 Wahlstrom A, Hugonin L, Peralvarez-Marin A, et al. Secondary structure conversions of Alzheimer's Abeta(1-40) peptide induced by membrane mimicking detergents. FEBS J.2008,275(20):5117-5128
81 Yoshiike Y.Minai R,Matsuo Y,et al. Amyloid oligomer conformation in a group of natively folded proteins. PLoS One,2008,3 (9):e3235
82 Jacobsen JS,Wu CC,Redwine JM,et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. ProcNatl Acad Sci USA,2006, 103(13):5161-5166
1 Blennow K, de Leon MJ,Zetterberg H. Alzheimer's disease. Lancet.2006 Jul 29,368 (9533):387-403
2郑元元,孙兰.阿尔采末病非人灵长类动物模型.中国药理学通报.2005,21(6)：649-653
3 Teng E, Stefanacci L, Squire LR, Zola SM. Constrasting effects on discrimination learning after hippocampal lesions and conjoint hippocampal can duate lesions in monkeys. J Neurosci,2000,20(10):3853-3863
4 Iijima K, Liu HP, Chiang AS,et,al.Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila:a potential model for Alzheimer's disease. Proc.Natl Acad.Sci USA.2004,101 (17):6623-6628
5 Iijima-Ando K, Hearn SA,Shenton C, et, al. Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One.2009,4(12):e8310
6谢宁,宋琳莉,牛英才,等.老年性痴呆动物模型研究进展及其评价.实验动物与比较医学,Mar.2006,26(1)：,50-53
7杨春壮,马彦文,刘长.老年性痴呆动物模型优劣浅析.牡丹江医学院学报,2003,24(3)：53-55
8 Francesc XS, Javier GC,Marta R, et al. Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence accelerated mice SAMP-8. Experimental Gerontology.2006,41 (4):360-367
9周伟勤,毕明刚,杜冠.快速老化小鼠SAMP8研究进展.中国药理学通报,2009,25(5)：565-568
10Yan Wu,Zhang AQ, Wai MS,et al. Changes of apoptosis related proteins in hippocampus of SAM mouse in development and aging. Neurobiology of Aging.2006, 27(5):1-10
11楚晋,李林.D-半乳糖致脑老化动物模型及其机理.中国康复理论与实践,2003,9(9)：521-522
12郭宗君,金丽英,郭云良,等.三种化学物质诱发大鼠认知障碍：优化阿尔茨海默病模型的研究.中国临床康复,2004,8(25)：5266-5268
13李守民,王婷婷,胡艳丽,等.D-乳糖调控SD大鼠海马巯醇抗氧化物(酶)致衰老的作用研究.昆明医学院学报,2009,(5)：1-5
14 Qin Hong-bing, Yang Zhao-ye, Fan Yi-jiang, Zhu Qing. Establishment and evaluation of aging models induced by D-galactose in mice. Journal of Clinical Rehabilitative Tissue Engineering Research,2009,13, (7):1275-1278
15冀俊虎,董联玲,曹娟,等.红景天对阿尔茨海默病大鼠行为学和脑组织抗氧化能力的影响.中国中医药信息杂志,2009,16(2)：38-40
16廉洁.复方地黄对大鼠学习记忆及海马CA1区神经元突触超微结构改变的实验研究.中华中医药学刊,2007,25(7)：1482-1483
17 Talesa VN. Acetylcholinesterase in Alzheimer's disease. Mechanisms of Ageing and Development,2001,122(16):1961-1969
18 Sisodia SS,Martin LJ, Walker LC. Cellular and molecular biology of Alzheimer' s disease and animal models. Neuroimaging Clin N Am.1995,5(1):59-68
19 Van Groen, Thomas, Kadish,et al. Transgenic AD model mice, effects of potential Anti-AD treatments on inflammation andpathology. Brain Reasearch Reviews.2005, 48 (2):370-378
20隋承光,尹元琴,任常山.Alzhemier病动物模型的构建及其分子病理学的变化.中国老年医学杂志,2005,25(9)：1069-1071
21邱幸凡,王平,袁德培.犀脑益智方对大鼠胆破能系统的影响.中医药学刊,2006,24(8)：1399-1440
22陆珊,雷亚平,王蓬文,等.APP5肽类似物i65对老年性痴幕模型大鼠行为学及PSD95和Shankl表达的影响.中国神经免疫学和神经病学杂志,2007,14(4)：183-184
23 Scalic C, Prosperi C, Vannucchi MG,et al. Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug:implication in Alzheimer's disease.Eur J Neurosci,2000,12:1900-1912
24杨勇,马龙,周晓辉,等.一种新型阿尔茨海默病动物模型的建立.新疆医科大学学报,2005,28(5)：399-404
25许妍姬.刺五加对痴呆模型小鼠记忆障碍及脑组织单胺氧化酶活性改变的保护作用.中成药,2009,31(8)：1290-1291
26方芳,晏勇,冯占辉,等.多因素损伤的老年性痴呆动物模型的实验研究.垂庆医学,2007,36(2)：146-148
27杨勇,马龙,周晓辉,洪玉.一种新型阿尔茨海默病动物模型的建立.新疆医科大学学报,2005,28(5)：399-404
28高丽萍,程书珍,王晓梅,贾丽霞.铝诱导阿尔茨海默病大鼠模型的建立.广东医学,2008,29(11)：1798-1800
29 Qian YH, Liu Y,Hu HT,et al.The effects of the total saponin of Dipsacus asperoides on the damage of cultured neurons induced by β-amyloid protein25-35. AnatSci Int,2002,77 (3):196-200
30杨杰,刘勇,钱亦华,等.β-淀粉样蛋白诱导大鼠海马S100 β表达的作用及机制.西安交通大学学报(医学版),2004,8(5)：322-325
31聂晶,罗勇,黄燮南.淫羊藿苷对淀粉样β蛋白片段25-35所致大鼠学习记忆障碍的改善作用.中国药理学与毒理学杂志,2008,22(1)：31-37
32楚晋,叶翠飞,李林,张丽.二苯乙烯苷对D-淀粉样肽致痴呆模型小鼠行为及胆碱能功能的影响.基础医学与临床,2006,26(2)：197-198
33楚晋,李林.脑室灌注β-淀粉样肽致痴呆动物模型.中国药理学通报,2004,20(7)：827-829
34张媛媛,李晓红,王敏,王栋.阿托伐他汀对Aβ(1-42)诱导AD模型抗凋亡作用的研究.中国老年学杂志,2009,29(5)：551-554
35张晓杰,.牛英才,兴桂华,等.通络救脑口服液对AD大鼠学习记忆能力及AChE表达的影响.中华中医药杂志,2007,22(6)：410-413
36臧艳平,马涤辉.β-七叶皂甙钠对老年性痴呆大鼠模型脑内炎症损伤的保护作用.中国神经免疫学和神经病学杂志,2007,14(4)：194-1961
37 Yamaguchi Y,Kawashima S. Effect of amyloid-β (25-35)on passive avoidance, radia-arm maze learning and choline acetyl-tranferase activity in the rat. Eur J Pharmacol,2001,412:(3):265-272
38 Pavia J.Alberch J, AlvarezI,et al. Repeated intracere broventricular administration of β-amyloid25-35 to rats decreases muscarinic receptors in cerebral cortex. Neurosci Lett,2000,278(122):69-72
39 Duyckaerts C,Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences. Acta Neuropathol,2008,115 (1): 5-38
40 Frautschy SA, Yang F, Irrizarry M, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol.1998,152 (1):307-317
41 Lefterov I.Bookout A, Wang Z, et, al. Expression profiling in APP23 mouse brain:inhibition of Abet a amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener.2007,22 (2)20
42 Lefterov I, Fitz NF, Cronican A, et al. Memory deficits in APP23/Abcal+/-mice correlate with the level of Abeta oligomers. ASN Neuro.2009,30;1 (2)pii:e00006
43 Daumas S.Sandin J, Chen KS,et al.Faster forgetting contributes to impaired spatial memory in the PDAPP mouse:deficit in memory retrieval associated with increased sensitivity to interference? Learn Mem.2008,26; 15(9):625-632
44 Ambree O, Leimer U, Herring A, et, al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice:involvement of multiple pathways. Am J Pathol.2006,169 (2):544-552
45 Fagan AM, Watson M, Parsadanian M, et al. Human and murine ApoE markedly alters A β metabolism before and after plaque formation in a mouse model of Alzheimer' s disease. Neurobiology of Disease,2002,9:305-318
46唐军,徐海伟,周光纪等.阿尔茨海默病转基因小鼠的研究现状与展望.中国行为医学科学,2006,15<2)：190-192
47应春怡,陈系古,陈汝筑等.神经系统退行性疾病相关的Tau蛋白及其转基因动物模型.中华神经医学杂志,2005,4(1)：100-103
48 Lin WL, Lewis J, Yen SH, et al. Filamentous tau in oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation. Am J Pathol.2003,162(1):213-218
49 Ramsden M, Kotilinek L, Forster C, et al. Age-dependent neurofibril ary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci.2005,25(46):10637-10647
50 Leroy K, Bretteville A,Schindowski K,et al. Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice.2007,171(3):976-992
51 Ke YD,Delerue F, Gladbach A, et al. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease.PLoS One.2009,4(11):e7917
52 Das HK. Transcriptional regulation of the presenilin-1 gene:implication in Alzheimer's disease. Front Biosci.2008,13:822-832
53JanusC, Amelio SD, AmitayO, et al. Spatial learning in transgenic mice expressing human presenilinl (PS1) transgenes. Neurobiology of aging.2000,21:541-549
54 Malik B, Currais A, Andres A, et al. Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the presenilin-1 Alzheimer's disease brain. Cell Cycle.2008,7(5):637-646
55 Cedazo-Minguez A.Apolipoprotein E and Alzheimer's disease:molecular mechanisms and therapeutic opportunities.J Cell Mol Med.2007,11(6):1227-38
56 Ezra Y, Oron L, Moskovich L,et al. Apolipoprotein E4 decreases where as apolipoprotein E3 increases the level of secreted amyloid precursor protein after closed head injury. Neuroscience,2003,121:315-325
57李达兵,唐军,范晓棠,等.PS1/APP双转基因AD模型小鼠与Aβ1-40海马注射AD模型大鼠的组织病理学比较.第三军医大学学报,2006,28(16)：1648-1651
58 Ribe EM, Perez M, Puiq B, et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis.2005,20 (3):814-822
59夏春梅,龚琦,傅燕,等.阿尔茨海默病双表达转基因小鼠(hAPP/hACHE)模型的初步建立.实验动物与比较医学,2007,27(2)127-129,136
60 Samura E, Shoji M, Kawarabayashi T, et al. Enhanced accumulation of tau in doubly transgenic mice expressing mutant beta APP and presenilin-1. Brain Res,2006,1094(1):192-199
61 Lewis J,Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science,2001,293 (5534):1487
62 Wirths O, Weis J, Szczygielski J, et al. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease.Acta Neuropathol (Berl),2006,111 (4):312-319
63 Oddo S, Caccamo AKitazawa M, et al. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobigy of Aging.2003,24(8):1063-1070
64 Oddo S, Caccamo A, Jason D, et al. Triplet transgenic Model of Alzheimer's Disease with Plaques and Tangles:Intracellular A β and Synaptic Dysfunction. Neuron(S0896-6273),2003,39:409-421
65 Rhein V, Song X,Wiesner A,et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl:Acad Sci USA.2009,106 (47):20057,-20062
66郑妮,汤宇,黎赛,等：新型复合式老年痴呆小鼠模型的建立.中南药学,2009,7(7)：481-484
67杨晓娟,张生林,陈芸,等.新型复合式老年痴呆动物模型的建立.Chisese journal of integrative medicine of cardio cerebrovascular disease,2006,4 (4):318-320
68曾芳,余曙光,唐勇,等.老年性痴呆复合动物模型研究概况.中国神经免疫学和神经病学杂志,2007,14(4)：197-200
69 Schuster D, Ra jendran A,Hui SW,et al. Protective effect ofcolostrinin on neuroblastoma cell survival is due to reduced aggregation of beta-amyloid. Neuropep tides,2005,39 (4):419-426
70 Nagai Y, Ogasawara A, Heese K. Possiblemechanisms ofAbeta (1-40) orA beta (1-42) induced cell death and their rescue factors. Nippon Yakurigaku Zasshi,2004, 124(3):135
71 Yun SW,Kouznetsova E,Nitschke C, et al. beta-Amyloid deposition and prion infection in adult primary brain cell long-,term culture model. Biochem Biophys Res Commun.2007,360(3):520-524
72张大鹏,陈云波,王奇,等.人参皂苷Rg1对淀粉样β蛋白诱导大鼠海马神经元损伤的保.中国临床康复,2006,10(23)：139-42
73王玉,万海同,严伟民,等.川芎嗪与葛根素合用对海马神经元损伤后的影响.中国中药杂志,2008,33(4)：424-427
74陈勤,李磊珂.远志皂苷对β淀粉样蛋白1-40诱导的体外培养皮层神经细胞损伤的保护作用.中国中药杂志,2007,32(13)：1336-1339
75 Lambert MP, Stevens G, Sabo S, et al. Beta/A4-ecoked degeneration of differentiated SH-SY5Y human neuroblastoma cells. J Neurosci Res,1994,39 (4): 377-385
76沈杰,陈晓春,林旭,张静.SH-SY5Y细胞高表达糖原合成激酶3β对tau蛋白磷酸化和微管稳定性的影响.中国病理生理杂志,2009,25(2)：254-258
77 Hong XJ, Yong J, Yan R, et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid protein in cultured cells. Neurosci Lett,2004, 367:123-128
78 Fang BY, Jia LF, Jia J P. Chinese Presenilinl V97L mutation enhanced A β 42 levels in SH-SY5Y neuroblastoma cells. NeurosciLett,2006,06:33-37
79杨潘,宋秋洁,王月华,等.淫羊藿黄酮对APP695基因转染神经细胞β-淀粉样肽及β-分泌酶的影响.中国康复理论与实践,2009,15(2)：126-128
80邵世滨,丁岩,张亚伦,等.人参皂苷Rgl对Aβ25-35诱导的Alzheimer's病细胞模型作用的研究.中国老年学杂志,2007,27(24)：2378-2381
81王丽娜,夏文,杨玲玲等.开心散对Aβ25-35诱导损伤SH-N-K神经细胞的保护作用及机制.毒理学杂志,2007,21(1)：22-26
82谢朝阳,梅寒芳,祝其锋.p淀粉样肽25-35对PC细胞p53和bc1-2基因表达的影响.广东医学院学报,2005,23(2)：121-123
83黄忠仕,农嵩,谢海渊,等.二苯乙烯苷对Aβ25-35致NG108-15损伤的保护作用.右江医学,2008,36(5)：517-519
84吴蕾,陈云波,王奇,等.人参皂苷对Aβ25-35蛋白诱导的老年性痴呆体外模型NG108-15神经元细胞凋亡的抑制作用.广州中医药大学学报,2007,24(2)：126-131
1魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考.中华中医药杂志,2005.20(8)：496-498
2邓家刚,郝二伟,范丽丽,覃骊兰..中医药对老年性痴呆认识和防治的研究进展.辽宁中医杂志,2007,34(11)：1659-1661
3郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
4邢长伟,张学峰,王景洪.从肾论治老年性痴呆研究进展.陕西中医学院学报,2004,27(1)：72-74
5李敏才,胡振武,肖志宏,补肾益智方对痴呆型大鼠的学习记忆功能影响.临床和实验医学杂志.2006,5(10)：1525
6马世平,詹莹,瞿融.当归芍药散的抗氧化作用研究.中药药理与临床.2001,17(3)：1-3
7高影,李有田,郑学清.益脑通脉汤治疗老年性痴呆症50例疗效观察.中国老年学杂志,2006,26(1)：100-101
8何英,方卓.化痰开窍法在神经系统疾病中的临床应用.辽宁中医药大学学报,2007,9(1)：40-42
9王平,刘玲,石学敏,等.加味温胆汤对SAM-P/10老化痴呆鼠3个脑区兴奋性氨基酸的影响.中国医院药学杂志,2002,22(11)：645-648
10孙明杰,于友华.清热解毒中药防治老年性痴呆症之理论探讨.中国中医基础医学杂志,2003,9(2)：17,24
11张晓杰,牛英才,兴桂华,李澎涛.通络救脑口服液对AD大鼠学习记忆能力及AChE表达的影响.中华中医药杂志,2007,(6)：410-412
12张艺平,韩鹏.黄连解毒汤治疗脑病的药理研究及临床研究新进展.中华实用中西医杂志.2003,16(12)：1832-1834
13刘学源,赵伟康,徐品初,等.调心方对杏仁核注射Aβ25-35诱导的阿尔茨海默病模型大鼠的影响.中草药,2004,35(1)：50-53
14 Auld D S,Kornecook TJ, Bastianetto S, et al. Alzheimer's disease and the basal forebrain cholinergic system:relations to beta-amyloid peptides, cognition,and treatment strategies.Prog Neurobiol.2002,68 (3):209-245
15丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响.中国老年学杂志,2004,24(12)：1183-1185
16谢宁,何秀丽,周妍妍,等.地黄饮子对老年痴呆模型大鼠行为学、AChE及Na+T+-ATP. Ca2+-ATP酶活性的影响.中医药学刊,2004,22(7)：1162-1163
17李玺,张英泽,张智燕,等.脑尔康对Alzheimer病小鼠脑细胞凋亡相关基因表达的影响.中国老年学杂志,2004,24(5)：433-434
18 Wang R, Tang XC. Neuroprotective effects of huperzine a natural cholinesterase inhibitor for the treatment of Alzheimer's disease. Neurosignals.2005,14(1-2): 71-82
18王子玫,孙启祥,刘庆丰,等.ZDY102对痴呆大鼠脑M受体的影响.中国药理学通报,2004,20：997-100
20钟振国,屈振国,王乃平,等.三七总皂苷对Alzheimer's病大鼠模型大脑胆碱能神经病理损害的保护作用.中药材,2005,28(2)：119-122
21 Hongxiao Jia,Yong Jiang,Yan Ruana,et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid-protein incultured cells. Neuroscience Letters,2004,367:123-128
22吴永强,姚文兵,高向东,等.红景天提取物对小鼠记忆获得性障碍的改善作用.中国药科大学学报,2004,35(1)：69-72
23 Manuel Buttini, Eliezer Masliah, Robin Barbour,et al. Beta-Amyloid Immuno-therapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease. The Journal of Neuroscience.2005,25 (40):9096-9101
24王春艳,郭景森,田晶,崔万丽.β淀粉样蛋白与阿尔茨海默病.吉林医药学院学报,2009,30(2)：99-102
25余锐,肖飞,李晓光,等.去痴灵脂溶性提取物血清抑制M146L细胞分泌β淀粉样蛋白.中国新药杂志,2006,15(13)：1061-1063
26张婷,董克礼.益智健脑颗粒对阿尔茨海默病患者脑脊液β淀粉样蛋白含量的影响.中国老年学杂志,2007,27(6)：1080-1081
27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.中国老年学杂志,2006,26(7)：924-926
28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淀粉样蛋白及前体蛋白的影响.北京中医药大学学报,2009,32(8)：553-556
29周忠光,韩玉生,姜国华.补气活血方对多因素损伤AD大鼠血清β淀粉样蛋白细胞因子的影响.中医药学报,2007,35(2)：16-18
30熊平,蒋灵芝,黄兆胜.补肾活血化痰中药复方对D-半乳糖诱发衰老模型大鼠中枢神经递质及β-淀粉样蛋白的影响.中国实验方剂学杂志,2007,13(2)：42-45
31江励华,段金廒,王明艳,等.华佗健聪汤药物血清对Aβ所致神经元损伤保护作用的实验研究.中国中医药科技,2009,16(1)：46-48
32朱未名,胡海燕.清心开窍方对 年痴呆小鼠脑自由基代谢及海马CA1区神经细胞形态的影响.中国实验方剂学杂志,2007,13(10)：57-60
32谢宁,宋琳,牛英才,等.加减地黄饮子对Aβ1-40所致AD大鼠学习记忆及抗氧化作用的影响.中医药学刊,2005,23(2)：212-214
33 Egashira N, Iwasaki K,Akiyoshi Y, et al. Protective effect of Toki-shakuyaku-san on amyloid beta25-35 induced neuronal damage in cultured rat cortical neurons. Phytother. Res,2005,19 (5):450-453
34周永其,邓湘平,顾振纶.石杉碱甲对氧自由基的影响.中国野生植物资源,2004,23(2)：44-45
35黄可儿,柯雪红,陈为,等.醒神液对老年性痴呆大鼠模型脑内神经递质的影响.中国老年学杂志,2003,23(11)：775-776
36罗喜荣,李红艳,郝小燕.天参益智方对老年性痴呆模型大鼠中枢神经递质的影响.中药药理与临床,2007,23(1)：65-67
37 Heneka MT,O' Banion MK. Inflammatory processes in Alzheimer's disease. Neuroimmunol,2007,184 (122):69-91
38 Vasto S, Candore G, Listi F, et al. Inflammation, genes and zinc in Alzheimer's disease. Brain Res Rev,2008,58 (1):96-105
39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.药药理与临床,2006,22(2)：48-49
40宋琳,安平,‘朴钟源,等.地黄饮子对老年性痴呆模型大鼠的学习记忆及炎性反应的影响.时珍国医国药,200718(7)：1654-1656
41林丽莉,宋秋洁,叶翠飞,等.淫羊藿黄酮对阿尔茨海默病模型神经炎性反应的影响.中国康复理论与实践,2009,15(2)：123-125
42孟燕,王蓉,刘梦霞,盛树力.阿尔茨海默病患者脑神经元调亡机制中的相关因素研究.中华老年医学杂志,2006,25(4)：245-247
43王珏,林胜友.中药抑制细胞凋亡的研究进展.云南中医中药杂志,2007,28(11)：46-48
44钱云飞,姚文兵,王华,等.开心散抑制过氧化氢诱导的PCI2细胞凋亡的机制.中国天然药物,2007,9(5)：379-384
45谢宁,邹纯朴,牛英才,等.地黄饮子对海马神经SAD模型细胞凋亡的调控作用.中国实验方剂学杂志,2004,10(4)：29-33
46谢宁,宋琳,姚丽芬,等.地黄饮子对阿尔茨海默病模型鼠脑神经元细胞凋亡及超微结构的影响.中国临床康复,2005,9(37)：93-95
47何明大,刘运林.脑灵汤对阿尔茨海默病模型鼠凋亡调控基因的影响.中国现代医学杂志,2005,15(22)：3398-3041
48胡亚萍,王平,胡永年,等.加味温胆汤含药脑脊液抗Aβ细胞毒性作用及其机制的实验研究.中国实验方剂学杂志,2007,13(7)：26-28
49谢桂琴,陈启盛.老年性痴呆的中药治疗现状.中国老年学杂志,2002,22(5)：4192-4211
50周爱玲,茅家慧,朱燕.药复方脑益康干预阿尔茨海默病模型小鼠脑组织神经生长因子及脑源性神经营养因子mRNA的表达.中国临床康复,2006,10(31)：16-18
51丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响.中国老年学杂志,2004,24(12)：1183-1185
52黄理钧,龚俊华,梁烨,等.益智健脑颗粒对AD模型大鼠学习记忆能力及海马神经元BDNF表达的影响.中国行为医学科学,2006,15(9)：780-783
53楚晋,叶翠飞,李林,等.二苯乙烯苷对D-半乳糖致脑老化小鼠学习记忆及神经营养因子的影响.中国药房,2005,16(1)：13-16
54张保平,刘畅,姜秀云.补肾活血化痰法对血管性痴呆大鼠单胺氧化酶及单胺类神经递质的影响.中西医结合心脑血管病杂志,2006,4(8)：94-695
55 Gao Guo-li,Che Guang-sheng, jiangyuan,et al. Effect of compound total extract ginseng and tall gastrodia tuber on content of monoamine transmitters in brain tissue of rats with vascular dementia. Chinese Journal of Clinical Rehabilitation.2006,10(19):182-183,186
56丛伟红,刘建勋,徐立,秦川.人参、银杏叶提取物对PDAPPV717I转基因小鼠海马乙酰胆碱和单胺类神经递质水平的影响.中国中西医结合杂志,2007,27(9)：810-813
57陈建宗,黄晨,高建苑,等.银杏叶提取物对老龄大鼠学习、记忆及有关神经递质的影响.成都中医药大学学报,2004,27(3)：27-28
58 Koo BS, Kwon TS, Kim CH. Salviae miltiorrhizae radix inhibits superoxide generation by activated rat microglias and mimics theaction of amphetamine on in vitro rat striatal dopamine release. Neurochem Res,2004,29(10):1837-1845
60吴尚霖,卞慧敏.酸枣仁油对小鼠学习记忆的影响.中草药,2001,32(3)：246-247
61郭蓉,曹云鹏.雌激素在阿尔茨海默病中的作用研究进展.国外医学.老年医学分册,2007,28(3)：97-100
62姜小帆,曾进.中医药防治阿尔茨海默病的实验研究思路及进展.现代中医药,2006,26(1)：58-60
63方芳,黄敏丽,陈行,等.雌激素对雌性去势大鼠脑组织抗氧化能力的影响.复旦学报(医学版),2004,31(1)：59-62
64周伟勤,邓景岳,毕明刚,杜冠华.淫羊藿苷改善快速老化小鼠SAMP8学习记忆多能及与血清雌激素水平相关性研究.中国实验方剂学杂志,2009,15(9)：38-41
65 Gong CX, Liu F, Grundke-IqbalI,et al.Post translational modifications of tau protein in Alzheimer's disease. JNeural Transm,2005,112 (6):813-838
66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.苏州大学学报(医学版)2009,29(3)：426-429
67 Chauhan NB. Effect of aged garlic extract on APP processing and tauphospho-rylation in Alzheimer's transgenic model Tg2576.J Ethnopharmacol,2006,108: 385-394.
68杨仙凌.治疗老年性痴呆的中药研究进展.浙江中医药大学学报,2007,31(1)：138-140
69王珍.中药抗阿尔茨海默病实验研究进展.现代中西医结合杂志,2008,17(17)：2743-2745
70邓家刚,郝二伟,郭宏伟,柳俊辉.老年性痴呆复方用药规律探讨.山东中医杂志,2007,26(6)：363-364
71周鲁,张卫华,曾令航,贾波.老年性痴呆的复方用药规律研究.辽宁中医杂志,2005,32(3)：243-244
1 Blennow K, de LeonM J,Zetterberg H. Alzheimer's disease. Lancet.2006,368 (9533):387-403
2尹宗宁.中医药防治老年痴呆症的研究进展.中国老年学杂志,2005,25(3)：3545-356
3李慧.中医中药对阿尔茨海默病的干预作用.中国中药杂志,2008,33(21)：2449-2453
4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.中国康复理论与实践,2005,11(5)：324-326
5秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
6陈春富,郎森阳,徐云燕,等.脱氢表雄酮对衰老大鼠体质量和学习记忆的影响.中国临床康复,2006,10(1)：77-79
7王跃春,王子栋,孙黎明,等.动物学习记忆能力的Y-型迷宫测试法.暨南大学学报(自然科学版),2001,22(5)：137-140
8薛承景,李建民.学习和记忆研究的行为学方法论述.河北医药,2007,29(1)：77-78
9秦川,朱华,常洋,高虹.阿尔茨海默症转基因小鼠的初步行为学评价.上海实验动物科学,2000,20(4)：210-212
10杜怡峰,王蓉,姬志娟,盛树力.APP17肽对APP转基因小鼠：学习记忆能力和海马神经细胞凋亡的影响.中国神经免疫学和神经病学杂志,2007,14(1)：7-10
11楚晋,李林,叶翠飞,等.淫羊藿黄酮对APP转基因小鼠学习记忆及β-amyloid生成的影响.中国科学技术大学学报,2008,38(4)339-448
12张兰,邢颖,赵玲,等.不同时程APP转基因小鼠学习记忆改变及参乌胶囊、二苯乙烯苷。的干预作用.中国行为医学科学,2006,15(3)：193-196
13 Dewachter I, Van Dorpe J, Smeijers L, et al. Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilinl. Journal of Neuroscience,2000,20 (17):6452-6458
14 Buckaer RL. Memory and executive function in aging and AD:multiple factors that cause decline and reserve factors that compensate. Neuron,2004,44 (1): 195-208
15朱庄庄,刘昌敏,冯丽.中医药治疗老年痴呆症的研究进展.中国临床康复,2004,18(13)：2598-2600
16邓家刚,郝二伟,范丽丽,覃骊兰.中医药对老年性痴呆认识和防治的研究进展.辽宁中医杂志,2007,34(11)：1659-1661
1 Tanzi RE, Bertram L. Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective. Cell,2005,120(4):545:555-1063
2 Thinakaran G, Koo EH. Amyloid Precursor Protein Trafficking, Processing, and Function. J Biol Chem.2008 October31,283 (44):29615-29619
3 Forman MS, Trojanowski JQ,Lee VM, et al. Neurodegenerative diseases:A decade of discoverie spaves the way for therapeutic breakthroughs. NatMed,2004,10: 1055-1063
4田金洲,徐意,时晶.中药干预β淀粉样肽生成、代谢及其毒性作用的研究概况.中国老年学杂志,2006,26(4)：557-560
45袁彪,叶冰,董青青,黄国钧.老年性痴呆动物模型的研究进展.实验动物科学,2009,26(1)：45-48
6 Duyckaerts C, Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences. Acta Neuropathol,2008,115 (1):5-38
7 Hooper NM. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prionprotein. Biochem Soc Trans,2005,33:335-338
8 Fukumoto H, Cheung BS, Hyman BT, et al. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol,2002,59:1367-1368
9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.上海实验动物科学,2000,20(4)：210-212
10秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
11 Tang X, Milyavsky M, Goldfinger N, Rotter V. Amyloid beta precursor like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress. Oncogene,2007,26(52):7302-7312
12Masliah E, Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer' s disease. J Alzheimers Dis,2006,9 (Supp13):91-99
13 Thinakaran G,Koo EH.Amyloid Precursor Protein Trafficking, Processing, and Function. J Biol Chem.2008 October31,283 (44):29615-29619
14 Wu Y, Ji SR,Jiang WL, et al. Comparison of the aggregation of beta-amyloid peptidel-42 and beta-amyloid peptidel-40. J Chin ElectrMicroscopy Soc,2003, 22:212-251
15 Wirths 0, Multhaup G, Bayer et al.A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide:the first step of a fatal cascade.J Neurochem,2004,91:513-520
16 Luo Y. BACE(Beta-secretase) knockout mice do not acquire compensatory gene expression changes ordevelop neural lesions over time.Neurobiol Dis 2003, 14:81-88
17 Richardson JC,Kendal CE,Anderson R.Ultrastructural and behavioral changes precede amyloid deposition in a transgenic model of Alzheimer's disease. Neurosci,2003,122:213-228
18 Squire LR,Zola SM. Structure and function of declarative and nondeclarative memory systems. ProcNatlAcad Sci USA,1996,93(24):13515-1352
19 Oddo S, Caccamo A, Tseng B, et al. Blocking Abeta42 accumulation delays the onset and progression of tau pathologyvia the C terminus of heat shock protein70-interacting protein:a mechanistic link between Abeta and tau pathology. JNeurosci,2008,28(47):12163-12175
20 Georganopoulou DG. Nanoparticle based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease.Proc Natl Acad Sci USA,2005,102:2273-2276
21俞建洪,尹其华,刘慧英,等.血清、脑脊液Tau蛋白与β-淀粉样蛋白浓度在早期AD、VD患者的对照研究.心脑血管病防治,2009,9(2)：128-130
22张雪玲,丁新生,程虹,等.脑脊液中Aβ检测对老年期痴呆早期诊断的意义.现代中西医结合杂志,2003,12(8)：789-792
23 Lewczuk P, Esselmann H,OttoM,et al.Neurochemical diagnosis of Alzheimer's dementia by CSF Abeta42, Abete42/Abeta40 ratio and total tau. Neurobiol Aging,2004,25(3):273-281。
24 Strozyk D, Blennow K, White LR, et al.CSF Abeta42 levels correlate with amyloid neuropathology in a population based autopsy study. Neurology,2003,60(4): 652-656
25 Fagan AM,Mintun MA,Mach RH,et al.Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol,2006,59 (3): 512-519
1秦川,朱华,张兵林,等.阿尔茨海默病学及转基因动物模型脑组织病理免疫组化研究.中国实验动物学报,2000,8：213-217
2 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356
3张癸荣,高登莲,殷明.Aβ的神经毒性与阿尔茨海默病的研究进展.解放军药学学报,2004,20(1)：58-61
4郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
5 Sgourakis NG, Yan Y,McCallum SA,et al.The Alzheimer's peptides A β 40 and 42 adopt distinct conformations in water:a combined MD/NMR study. J Mol Biol.2007, 368 (5):1448-1457
6 Lacor PN, Buniel MC, Furlow PW, et al.Abeta oligomer-induced aberrations in synapse composite on, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci.2007,27 (4):796-807
7Wahlstrom A, Hugonin L,Peralvarez-Marin A, et al. Secondary structure conversions of Alzheimer's Abeta(1-40) peptide induced by membrane mimicking detergents. FEBS J,2008,275 (20):5117-5128
8 Bresler T, Shapira M, Boeckers T, et al. Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly. J Neurosci,2004, 24(6):1507-1520
9 Bourne JN, Harris KM. Balancing structure and function athippocampal dendritic spines. Annu RevNeurosci,2008,31:47-67
10 Yoshiike Y,Mina i R,Matsuo Y, et al.Amyloid oligomer conformation in a group of natively folded proteins. PLoS One,2008,3(9):e3235
11 Deshpande A, Mina E, Glabe C, et al.Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci.2006,26 (22):6011-6018
12 Coleman P,Federoff H, Kurlan R. A focus on the synapse forneuro protection in Alzheimer disease and other dementias. Neurology,2004,63:1155-1162
13张雷明,田金洲,尹军祥,等.中药复方金思维对APPV717 I转基因小鼠海马神经损伤的保护作用.中草药,2009,40(3)：410-415
14 Henze DA, McMahond BT, Harris KM, et al. Giant miniature EPSCs at the hippocampal mossy fiber to CA3 pyramidal cell synapse are monoquantal.J Neurophysiol,2002, 87:15-29:
15 Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer's disease. Prog Neurop Sychophaimacol BiolPsychiatry,2005,29:407-101
16 Manczak M, Anekonda TS, Henson E, et al. Mitochondria are a direct site of A β accumulation in Alzheimer's disease neurons:implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics, 2006,15(9):1437-1449
17辛颖.线粒体与神经退行性病变.医学综述,2008,14(4)：.520-521
18 Takahashi RH, Almeida CG, Kearney PF,et al. Oligomerization of Alzheimer's β-amyloid within processes and synapses of cultured neurons and brain. J of Neurosci,2004,24(14):3592-3599
19 LaFerla FM, Green KN,Oddo S.Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci,2007,8(7):499-509
20 Cook DG, FormanMS,Sung JC, et al. Alzheimer's A beta (1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. NatMed, 1997,3(9):1021-1031
21Vieira HL, Belzacq AS,Haouzi D,et al.The adenine nucleotide translocator:a target of nitric oxide,peroxynitrite,and 4-hydroxynonenal, Oncogene,2001, 20(32):4305-4316
22 Lustbader JW,Cirilli M, Lin C, et al.ABAD directly links A β to mitochondrial toxicity in Alzheimer's disease. Science,2004,304 (1):448-452
23 Lustbader JW, CirilliM,Lin C, et al.ABAD directly links to mitochondrial toxicity in Alzheimer's disease. Science,2004; 304 (5669):448-452
24 Casley C S, Land J M,Sharpe MA,et al. β-amyloid fragment25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis,2002, 10(3):258-267
25葛振英,石纯,许晓伍,等.雌激素撤退大鼠海马和基底前脑神经元线粒体超微结构学观察.解剖学研究,2006,28(2)131-133
26 Hirai K.Aliev G, Nunomura A,et al. Mitochondrial abnormalities in Alzheimer' s disease. J Neurosci.2001,21(9):3017-3023
27 Zhu X, Smith MA, Perry G, et al. Mitochondrial failures in Alzheimer's disease. AmJ Alzheimers Dis Other Demen,2004,19 (6):345-352
28 Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications. Ann Neurol,2005; 57 (5):695-703
29 Sullivan PG,Brown MR. Mitochondrial aging and dysfunction in Alzheimer's disease. Prog Neurop Sychophaimacol BiolPsychiatry,2005; 29:407-410
30 Blass J P. Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res.2001,66(5):851-856
31 Mattson MP. Pathways towards and away fromAlzheimer's disease. Nature,2004, 430(7000):631-639
32 Cardoso SM, Santana I.SwerdLow RH, et al. Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity. J Neurochem,2004,89(6): 1417-1426
31Kanaan NM, Kordower JH, Collier TJ. Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamineneurons:relevance to selective neuronal vulnerability.J CompNeurol,2007,10; 502 (5):683-700
33 Castejon OJ. Lysosome abnormalities and lipofucsin content of nervecells of edematous human cerebral cortex. J Submicrosc CytolPathol,2004,36 (3-4):263-271
34 Petersen RC, Negash S. Mild cognitive impairment:an overview. CNS Spectr,2008, 13(1):45-53
35朱轶冰,陆佩华,盛祖杭.AD发病机制的新探索：轴浆运输障碍假说.生理科学进展,2008,39_(1)：5-9
36崔德芝,张恭新,朱振铎.老年性痴呆的中医理论探讨.山东中医杂志：2006,25(10)：655-657
37黄亮,黄燕.血脑屏障功能的中医药研究现状.中医药学刊,2005,23(9)：1648-1650
1 Pereira C,Ferreiro E, Cardoso SM,et al.Cell degeneration induced by amyloid-beta peptides:Implications for Alzheimer's disease. J Mol Neurosci, 2004,23(1-2):97-104
2 Kawasumi M, Hashimoto Y,Chiba T,et al. Molecular mechanisms for neuronal cell death by Alzheimer's amyloid precursor protein-relevant insults. Neurosignals, 2002:236-250
3吕良,钟振国.阿尔茨海默病淀粉样β蛋白诱导神经元凋亡的研究进展.中西医结合心脑血管病杂志,2007,5(6)：517-519
4朱汉华,李浪,汪熠,等.TUNEL检测心肌细胞凋亡的影响因素探讨.广西医科大学学报,2009,26(1)：24-26
5 Zhu Y, Xu J, Kwong WH, et al. Microscopic analysis of the different regions of three Alzheimer brains aged 93,94, and 104 years old (J). Int.J Neurosci.2007, 117(10):1403-1413
6 Affar EB, Germain M, Winstall E, et al. Caspase3 mediated processing of poly (ADP-ribose) glycohydrolase during apoptosis.J BiolChem,2001,276 (4): 2935-2942
7 Boatright KM, Salvesev GS.Mechanisms of caspase activation. Curr Opin Cell Biol,2003,15(6):725-731
8 Eckert A, Marques CA, Keil U. Increased apoptotic cell death in sporadic and genetic Alzheimer's disease. Ann N Y Acad Sci.2003,1010:604-609.
9胡胜全,余惠,刘塔斯,杨大坚.人参水提物对β淀粉样蛋白诱导SH-SY5Y细胞凋亡的保护作用.时珍国医国药,2009,.20(2)：257-259
10苏心,张文治.β-淀粉样蛋白致胚胎鼠大脑神经干细胞凋亡作用的研究,中国现代神经疾病杂志,2005,5(4)：248-251
11杨戈,林水淼,赵伟,等.调心方有效部位对类AD大鼠脑组织凋亡信号转导分子Caspase-3及凋亡相关基因bc 1-2、 baxmRNA表达的影响.中国中西医结合杂志,200626(2):147-151
12 BehlC, Moosmann B. Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds. Biol Chem,2002,383(3-4):521-536
13 Francois GG,Daigen X,George S, et al.Involvement of caspases Inproteolytic cleavage of Alzheimer's amloid-precursor protein and amyloidogenic A β peptide formation. Cell,1999,97(4):395-406
14叶静,刘协和,邓红,等.β-淀粉样多肽诱导神经元凋亡和Caspase-3蛋白表达的实验研究.中国中西医结合杂志,2006,26(2)：147-151
15庄莹,陈杰.阿尔茨海默病病因及发病机制研究进展.吉林医药学院学报,2008,29(4)：101-104
16李龙宣,许志恩,赵斌,等.Alzheimer病患者脑脊液中炎前和抗炎细胞因子以及凋亡信号分子的变化.中国神经免疫学和神经病学杂志,2005,12(4)：212-215
17宋建德,袁丽萍,梁勇,等.药用植物多糖的免疫作用研究进展.中兽医医药杂志,2004,2：22-24
18李刚,曾祥发,陆晖,李芳.石菖蒲健脑益智作用的研究进展.广西中医学院学报,2009,12(1)：74-76
1 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356
2 Yanker BA, Duffy L K, Kirschner DA. Neurotrophicand neurotoxic effects of amyloid protein:reversal by tachykinin neuroprptide. Science,1990,250 (4978):279-282
3钱亦华,史利利,杨杰,等.原代培养小鼠皮层神经细胞对淀粉样蛋白的内化作用.中南大学学报(医学版),2008,33(11)：1019-1027
4 Schuster D, Rajendran A, Hui SW, et al. Protective effect ofolostrinin on neuroblastoma cell survival is due to reduced aggregation of beta amyloid. Neuropep tides,2005,39 (4):419-426
5 Nagai Y, Ogasawara A,Heese K.Possible mechanisms of A beta(1-40) or A beta (1-42)-induced cell death and their rescue factors. Nippon Yakurigaku Zasshi,2004,124(3):135-143
4魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考.中华中医药杂志,2005,20(8)：496-498
6郑明荣,郝百鸣.中医药治疗老年性痴呆研究进展.浙江中西医结合杂志,2008,18(1)：65-67
7吴庆四,徐东芳,刘冬梅,等.糖皮质激素促β-淀粉样蛋白致海马神经元损伤.中国神经精神疾病杂志,2008,34(3)：178-180
8 Tomohiro Chiba, Marina Yamada, Yuichi Hashimoto, et al. Development of a femtomolar acting human in derivative named colivel in by attaching activity dependent neurotrophic factor to its N terminus:characterization of colivelin mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo. The Journal of Neuroscience,2005,25(44):10252-10261
9邵世滨,丁岩,张亚伦,等.人参皂苷Rgl对Aβ25-35诱导的Alzheimer's病细胞模型作用的研究.中国老年学杂志,2007,27(24)：2378-2381
10王玉,万海同,严伟民,等.川芎嗪与葛根素合用对海马神经元损伤后的影响.中国中药杂志,2008,33(4)：424-427
11张魁华,赖世隆,胡镜清,等.补肾益智方对AD细胞模型钙离子内流、细胞骨架、细胞凋亡的影响.中国中医基础医学杂志,2002,8(7)：23-25
12 Hashimoto M, Rockenstein E, Crews L, et al.Role of protein aggregationin mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson' s diseases. Neuromol Med,2003,4:21-36
13聂晶,罗勇,石京山.淫羊藿苷对Aβ25-35所致神经细胞损伤的保护作用研究.遵义医学院学报,2007,30(3)：229-231,235