通过两种痴呆症模型比较六味地黄颗粒和通络救脑滴丸的疗效特点
|
摘要
1.背景
老年痴呆症包括：轻度认知障碍、阿尔茨海默病(Alzheimer's disease,AD)、血管性痴呆,以及由其他疾病,如帕金森病等导致的痴呆,其中以AD患者最为多见。该病是以认知功能缺损为主要症状的疾病,常伴有精神、行为和人格异常,严重影响日常生活或工作能力。全球患病人数庞大,造成了巨大的社会、经济、家庭压力。现代医学研究表明,AD发病主要与β-淀粉样蛋白(amyloid-β, Aβ)在脑组织异常沉积、脑内神经血管单元(neurovascular unit,NVU)功能异常导致Aβ清除障碍、胆碱能神经元受损、氧化应激、神经炎症反应或基因突变等因素有关,为此研究者针对调节Aβ代谢、改善胆碱能神经元功能或抗氧化应激等多方面研制了多种药物,不过目前对该病的治疗尚无切实有效的措施。中医从整体出发,认为老年痴呆症的病位在脑,发病与肾、心、脾、肝等脏腑的功能失调有密切关系。其病因以内因为主,或因肾精亏耗、气血不足、痰瘀交阻,脑髓失养；或因七情内伤、久病耗损、年迈体虚,脑髓失充,而致气、血、痰、瘀等病邪为患。并由此制定了补肾填精,解郁散结的总体治法,临床发现多种中药复方对该病显示了独特的疗效。
本研究在老年痴呆症系“肾精不足”或“毒损脑络”而发病的中医病机指导下,结合两种拟老年痴呆症小鼠模型——肾虚精乏脑髓失充证(SAMP8小鼠)模型和毒损脑络证(双海马注射Aβ1-40的SAMR1小鼠)模型,探讨两种治疗老年痴呆症常用的不同功效中药复方——具有补肾填精功效的六味地黄颗粒(LWDH)和解毒通络功效的通络救脑滴丸(TLJN),对不同拟老年痴呆症模型的作用特点及可能的药效靶点,并比较这两种相同品系小鼠,在不同造模因素诱导下的神经行为学差异,寻找不同模型小鼠对造模因素反映的特征,以期为中药复方药效评价指标体系提供证据。
2.目的
1)确认增龄对两种拟老年痴呆症小鼠的影响；
2)比较两种拟老年痴呆症模型小鼠的神经行为学及发病相关病理环节的差异；
3)比较两种不同功效中药复方的作用特点,并根据动物模型的相关病理环节,寻找中药复方可能的药效靶点。
3.方法
1)使用行为学Morris水迷宫和跳台实验,比较2月龄、6月龄及8月龄Aβ注射模型和SAMP8模型与同月龄正常对照组在Morris水迷宫实验逃避潜伏期、寻台成功率、游速和跳台潜伏期、错误次数、错误区时间等指标的差异。
2)对8月龄Aβ注射模型和SAMP8模型,均设立对症给药和非对症给药组,即两种模型分别均给予LWDH和TLJN治疗,使用行为学Morris水迷宫和避暗实验,比较上述各组在Morris水迷宫实验逃避潜伏期、寻台成功率、游速和避暗潜伏期、错误次数、错误区时间等指标的差异。
3)使用免疫组织化学方法,标记上述各组小鼠脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE、apoE、α2M等Aβ代谢相关蛋白的表达情况,并比较不同功效中药复方治疗组的差异。
4)使用蛋白免疫印迹方法,分别检测上述各组小鼠海马和皮层APP、BACE1、IDE、LRP1、RAGE、apoE、α2M等蛋白的表达情况,并比较不同功效中药复方治疗组的差异。
4.结果
1)与对照组比较,8月龄Aβ注射模型和SAMP8模型在水迷宫逃避潜伏期、寻台成功率,跳台实验潜伏期、错误区时间及避暗实验潜伏期、错误次数、错误区时间等行为学检测指标,脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE、apoE和a2M等蛋白表达上,均表现出显著性差异。在跳台实验和避暗实验错误区时间这个指标上,8月龄Aβ注射模型与同月龄对照组相比有差异。在水迷宫游速这个指标上,8月龄SAMP8模型与同月龄对照组相比有差异。
2)两种模型之间,与8月龄Aβ注射模型比较,同月龄SAMP8模型在水迷宫游速,跳台潜伏期,避暗错误次数、错误区时间和脑组织APP(皮层)、BACE1(皮层)、IDE(皮层和海马)、LRP1(海马)、RAGE(皮层和海马)及apoE (皮层)蛋白表达上,有显著性差异。
3)对于8月龄Aβ注射模型而言,对症药物,即TLJN,在调节模型小鼠避暗潜伏期、错误次数、错误区时间等行为学检测指标,脑组织APP、BACE1、IDE、LRP1、RAGE和apoE等蛋白表达上,发挥了显著作用。对于8月龄SAMP8模型而言,对症药物,即LWDH,在调节模型小鼠水迷宫逃避潜伏期、寻台成功率和跳台实验潜伏期等行为学检测指标,脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE和α2M等指标上,发挥了显著作用。
4)两种不同功效中药复方治疗组之间,对于8月龄Aβ注射模型而言,对症药物TLJN在改善该模型小鼠避暗潜伏期及脑组织皮层和海马APP表达、皮层apoE表达、海马BACE1、IDE和RAGE表达水平上,发挥了显著作用,而非对症药物LWDH对上述指标的调节作用不如TLJN;对于8月龄SAMP8模型而言,对症药物LWDH在改善小鼠水迷宫寻台成功率、避暗潜伏期及脑组织皮层和海马APP、BACE1、IDE表达、海马Aβ表达水平上,发挥了显著作用,而非对症药物TLJN对上述指标的调节作用不如LWDH。
5.结论
1)增龄对SAMP8小鼠和双海马注射Aβ1-40的SAMR1小鼠行为学改变有显著影响。
2)不同证型的模型之间,8月龄Aβ注射模型和SAMP8模型,均表现出了空间学习记忆、对电刺激的记忆、被动逃避反应能力缺失,及Aβ代谢相关蛋白的表达异常。但是,与Aβ注射模型比较,SAMP8模型的活动度相关指标(如,水迷宫游速、避暗错误次数等)下降；增加脑内Aβ水平的相关蛋白(如APP、BACE1、RAGE等)表达更高；降低脑内Aβ水平的相关蛋白(如IDE、LRP1、apoE等)表达更低,反应了SAMP8模型Aβ代谢障碍更严重,及肾虚精乏证的行为学特征。
3)不同功效中药复方之间,对于8月龄Aβ注射模型和SAMP8模型,对症药物均发挥了纠正Aβ代谢障碍的作用,表现在降低Aβ生成相关蛋白APP和BACE1的表达；增加Aβ降解相关蛋白IDE的表达等。非对症药物对上述指标未发挥显著改善作用,甚至还有反作用。提示,脑组织APP、BACE1、IDE等与Aβ生成及降解相关的蛋白,可作为评价不同功效中药复方的特异性指标,反应药物的药效特点。
4)对于脑内清除Aβ的重要途径LRP1系统而言,在调节多数指标上,不同功效中药复方分别对两种模型,均发挥了作用,且作用趋势一致。仅在8月龄Aβ注射模型的皮层apoE、海马RAGE表达上,及SAMP8模型的皮层LRP1表达上,表现出了对症药物的优势。提示,可能因为LRP1和RAGE及apoE、α2M等蛋白之间有密切的相互作用,发生病理改变时,相互影响也更复杂,导致不同功效中药复方在不同模型上未显示出特异性疗效。但该系统指标可作为评价药物整体疗效的参考指标。
5)对于行为学相关指标而言,不同功效中药复方对两种证型的模型,在8月龄Aβ注射模型的避暗潜伏期、错误次数、错误区时间等指标,及SAMP8模型的水迷宫逃避潜伏期、寻台成功率和避暗潜伏期、错误次数等指标上,表现出了对症药物的优势。提示对症药物对于改善相应证候模型小鼠的空间学习记忆和被动逃避反应能力上有作用,有助于评价不同功效中药复方的药效特点。
总之,这两种拟老年痴呆症小鼠模型在Aβ代谢相关蛋白的表达和行为学上有各自的病理特点,不同功效中药复方对不同模型的起效靶点也有特异性,且对症给药对于改善模型行为学和Aβ生成及降解的环节上,发挥特异性作用,因此这些指标可作为评价不同功效中药复方药效的特异性指标。而LRP1系统的各指标,在两种模型上,未反映出不同功效中药复方的药效特点,作为评价指标,特异性欠佳。所以,对于中药复方药效评价指标而言,应根据药效特点和模型证候进行选择,以期更客观地评价中药复方药效,更准确地发现药物作用靶点和特点。
1. Backgroung
Dementia is a complex disease which be characterized by impairments in cognition and behavior. Behavioural and psychological symptoms of dementia are present in the course of the illness in most patients with dementia. The incidence of dementia among the elderly population is rising rapidly around the world. Due to the numerous cases of patients, there are more and more burden of society, economy and family. Alzheimer's disease(AD) is the leading type of dementia. AD is a neurodegenerative disorder of the aged that has multiple factors, which contribute to AD's etiology in terms of initiation and progression. There are several hypotheses have been formulated to explain this debilitating disease, and those hypotheses often have overlapping features. The best-known hypothesis to explain AD is the Amyloid Cascade Hypothesis which involves the role of the accumulation of amyloid-βpeptide(Aβ) in the brain. Other theories include Dysfunction of Neurovascular Unit which suggests manifold neurovascular pathogenic cascades for AD, cholinergic hypothesis, the role of oxidative stress or neuroinflammation, genes mutation and so on. Current therapeutics on the market, including cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists and productions of modulating Aβmetabolism, provide symptomatic relief but do not alter progression of this disease. Therefore, progress in the areas of prevention and disease modification may be important. Based on Traditongal Chinese medicine, dysfunction of brain, kidney, heart, spleen and liver all may due to AD.Deficiency of kidney essence, asthenia of qi and blood, sputum and blood stasis, internal injury due to seven emotions, prolonged illness consuming healthy qi all would impair the brain. The basic therapeutic methods is Invigorating kidney and supplementing essence, relieve accumulation and resolve stagnation. Traditongal Chinese medical prescriptions are multifunctioning that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD and have a better effection.
This experiment is guided by the pathogenesis theories of Consuming of Kidney Essence and Toxin Hurts Brain Collaterals to study SAMP8(model-P) & hippocampus injection of Aβ1-40 in SAMR1(model-A) models, to compare the actions of Liu Wei Dihuang granule(LWDH) and Tong Luo Jiunao dripping pill(TLJN), and to find the feature of those prescriptions.
2. Objective
1) To test the correlation of aging and cognition impairments in two models;
2) To compare the effect of behavioral test and morphology of two models;
3) To compare the speacil function of two prescriptions, and ascertain the potential drug targets.
3. Methods
1) To investigate the diversity of 2-month-old,6 month-old and 8 month-old SAMP8 and SAMR1 mice using Morris water maze and passive avoidance test(Step-up test).
2) To investigate the discrepancy of 8 month-old model-P and model-A treated by LWDH(PL group & AL group) and TLJN(PT group & AT group) using Morris water maze and passive avoidance test(Step-through test).
3) To compare the difference in all group on expression of Aβ,APP, BACE1, IDE, LRP1, RAGE, apoE and a2M using immunohistochemistry.
4) To compare the difference in all group on level of APP, BACE1, IDE, LRP1, RAGE, apoE and a2M using Weatern blotting.
4. Results
1) To compare with the N group, there are diversity in MWM escape latency, success rate and Step-up test latency, wrong frequency, and Step-though test latency, wrong frequency of 8-month-old model-P and model-A. To compare with the N group, there are diversity in both Step-up test and Step-though test wrong time of model-A. To compare with the N group, there are diversity in MWM swimming speed of model-P.
2) To compare with the A group, there are difference between model-A and model-P on MWM swimming speed, Step-up test wrong frequency, Step-though test wrong frequency, wrong time and expression of APP(cortex), BACE1(cortex), IDE(cortex and hippocampal), LRP1(hippocampal),RAGE(cortex and hippocampal) and apoE(cortex).
3) The irregular expression of Aβ, APP, BACE1, IDE, LRP1, RAGE, apoE and a2M in brains of model-P and model-A. The regulated expression of APP, BACE1, IDE, LRP1 RAGE and apoE were shown in AT group as well as the regulated expression of Aβ, APP, BACE1, IDE, LRP1, RAGE, and a2M were tested in PL group. TLJN have function on model-A by regulated Step-though test latency and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. LWDH have function on model-P by regulated MWM success rate, Step-though test latency and expression of Aβ,APP, BACE1, IDE and RAGE.
5. Conclusions
1) There are correlation of aging and cognition impairments in two models;
2) Model-P and model-A have severely impaired acquisition and retention of spatial learning task and passive avoidance response, and neurochemical. So SAMP8 maybe a more severely model.
3) These two traditongal Chinese medical prescriptions have significant effection, due to selecting of treatment based on the differential diagnosis. The expreesion of APP、BACE1、IDE coule be useful develop and evaluate potential new formulations.
4) There are few difference between LWDH and TLJN in clearance of Aβby LRP1 system. So the evaluation for traditongal Chinese medical prescriptions should be unambiguous.
5) The behavioral test maybe unsuitable as a evaluation for different traditongal Chinese medical prescriptions
In conclusion, SAMP8 and hippocampus injection of Aβ1-40 in SAMR1 mice have difference on MWM swimming speed, Step-up test wrong frequency, Step-though test wrong frequency, wrong time and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. To hippocampus injection of Aβ1-40 in SAMR1 mice, TLJN have function by regulated Step-though test latency, and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. On the other hand, to SAMP8 mice LWDH have function by regulated MWM success rate, Step-though test latency and expression of Aβ, APP, BACE1, IDE and RAGE. These two models and two traditongal Chinese medical prescriptions have their own characteristics.
老年痴呆症包括：轻度认知障碍、阿尔茨海默病(Alzheimer's disease,AD)、血管性痴呆,以及由其他疾病,如帕金森病等导致的痴呆,其中以AD患者最为多见。该病是以认知功能缺损为主要症状的疾病,常伴有精神、行为和人格异常,严重影响日常生活或工作能力。全球患病人数庞大,造成了巨大的社会、经济、家庭压力。现代医学研究表明,AD发病主要与β-淀粉样蛋白(amyloid-β, Aβ)在脑组织异常沉积、脑内神经血管单元(neurovascular unit,NVU)功能异常导致Aβ清除障碍、胆碱能神经元受损、氧化应激、神经炎症反应或基因突变等因素有关,为此研究者针对调节Aβ代谢、改善胆碱能神经元功能或抗氧化应激等多方面研制了多种药物,不过目前对该病的治疗尚无切实有效的措施。中医从整体出发,认为老年痴呆症的病位在脑,发病与肾、心、脾、肝等脏腑的功能失调有密切关系。其病因以内因为主,或因肾精亏耗、气血不足、痰瘀交阻,脑髓失养；或因七情内伤、久病耗损、年迈体虚,脑髓失充,而致气、血、痰、瘀等病邪为患。并由此制定了补肾填精,解郁散结的总体治法,临床发现多种中药复方对该病显示了独特的疗效。
本研究在老年痴呆症系“肾精不足”或“毒损脑络”而发病的中医病机指导下,结合两种拟老年痴呆症小鼠模型——肾虚精乏脑髓失充证(SAMP8小鼠)模型和毒损脑络证(双海马注射Aβ1-40的SAMR1小鼠)模型,探讨两种治疗老年痴呆症常用的不同功效中药复方——具有补肾填精功效的六味地黄颗粒(LWDH)和解毒通络功效的通络救脑滴丸(TLJN),对不同拟老年痴呆症模型的作用特点及可能的药效靶点,并比较这两种相同品系小鼠,在不同造模因素诱导下的神经行为学差异,寻找不同模型小鼠对造模因素反映的特征,以期为中药复方药效评价指标体系提供证据。
2.目的
1)确认增龄对两种拟老年痴呆症小鼠的影响；
2)比较两种拟老年痴呆症模型小鼠的神经行为学及发病相关病理环节的差异；
3)比较两种不同功效中药复方的作用特点,并根据动物模型的相关病理环节,寻找中药复方可能的药效靶点。
3.方法
1)使用行为学Morris水迷宫和跳台实验,比较2月龄、6月龄及8月龄Aβ注射模型和SAMP8模型与同月龄正常对照组在Morris水迷宫实验逃避潜伏期、寻台成功率、游速和跳台潜伏期、错误次数、错误区时间等指标的差异。
2)对8月龄Aβ注射模型和SAMP8模型,均设立对症给药和非对症给药组,即两种模型分别均给予LWDH和TLJN治疗,使用行为学Morris水迷宫和避暗实验,比较上述各组在Morris水迷宫实验逃避潜伏期、寻台成功率、游速和避暗潜伏期、错误次数、错误区时间等指标的差异。
3)使用免疫组织化学方法,标记上述各组小鼠脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE、apoE、α2M等Aβ代谢相关蛋白的表达情况,并比较不同功效中药复方治疗组的差异。
4)使用蛋白免疫印迹方法,分别检测上述各组小鼠海马和皮层APP、BACE1、IDE、LRP1、RAGE、apoE、α2M等蛋白的表达情况,并比较不同功效中药复方治疗组的差异。
4.结果
1)与对照组比较,8月龄Aβ注射模型和SAMP8模型在水迷宫逃避潜伏期、寻台成功率,跳台实验潜伏期、错误区时间及避暗实验潜伏期、错误次数、错误区时间等行为学检测指标,脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE、apoE和a2M等蛋白表达上,均表现出显著性差异。在跳台实验和避暗实验错误区时间这个指标上,8月龄Aβ注射模型与同月龄对照组相比有差异。在水迷宫游速这个指标上,8月龄SAMP8模型与同月龄对照组相比有差异。
2)两种模型之间,与8月龄Aβ注射模型比较,同月龄SAMP8模型在水迷宫游速,跳台潜伏期,避暗错误次数、错误区时间和脑组织APP(皮层)、BACE1(皮层)、IDE(皮层和海马)、LRP1(海马)、RAGE(皮层和海马)及apoE (皮层)蛋白表达上,有显著性差异。
3)对于8月龄Aβ注射模型而言,对症药物,即TLJN,在调节模型小鼠避暗潜伏期、错误次数、错误区时间等行为学检测指标,脑组织APP、BACE1、IDE、LRP1、RAGE和apoE等蛋白表达上,发挥了显著作用。对于8月龄SAMP8模型而言,对症药物,即LWDH,在调节模型小鼠水迷宫逃避潜伏期、寻台成功率和跳台实验潜伏期等行为学检测指标,脑组织Aβ、APP、BACE1、IDE、LRP1、RAGE和α2M等指标上,发挥了显著作用。
4)两种不同功效中药复方治疗组之间,对于8月龄Aβ注射模型而言,对症药物TLJN在改善该模型小鼠避暗潜伏期及脑组织皮层和海马APP表达、皮层apoE表达、海马BACE1、IDE和RAGE表达水平上,发挥了显著作用,而非对症药物LWDH对上述指标的调节作用不如TLJN;对于8月龄SAMP8模型而言,对症药物LWDH在改善小鼠水迷宫寻台成功率、避暗潜伏期及脑组织皮层和海马APP、BACE1、IDE表达、海马Aβ表达水平上,发挥了显著作用,而非对症药物TLJN对上述指标的调节作用不如LWDH。
5.结论
1)增龄对SAMP8小鼠和双海马注射Aβ1-40的SAMR1小鼠行为学改变有显著影响。
2)不同证型的模型之间,8月龄Aβ注射模型和SAMP8模型,均表现出了空间学习记忆、对电刺激的记忆、被动逃避反应能力缺失,及Aβ代谢相关蛋白的表达异常。但是,与Aβ注射模型比较,SAMP8模型的活动度相关指标(如,水迷宫游速、避暗错误次数等)下降；增加脑内Aβ水平的相关蛋白(如APP、BACE1、RAGE等)表达更高；降低脑内Aβ水平的相关蛋白(如IDE、LRP1、apoE等)表达更低,反应了SAMP8模型Aβ代谢障碍更严重,及肾虚精乏证的行为学特征。
3)不同功效中药复方之间,对于8月龄Aβ注射模型和SAMP8模型,对症药物均发挥了纠正Aβ代谢障碍的作用,表现在降低Aβ生成相关蛋白APP和BACE1的表达；增加Aβ降解相关蛋白IDE的表达等。非对症药物对上述指标未发挥显著改善作用,甚至还有反作用。提示,脑组织APP、BACE1、IDE等与Aβ生成及降解相关的蛋白,可作为评价不同功效中药复方的特异性指标,反应药物的药效特点。
4)对于脑内清除Aβ的重要途径LRP1系统而言,在调节多数指标上,不同功效中药复方分别对两种模型,均发挥了作用,且作用趋势一致。仅在8月龄Aβ注射模型的皮层apoE、海马RAGE表达上,及SAMP8模型的皮层LRP1表达上,表现出了对症药物的优势。提示,可能因为LRP1和RAGE及apoE、α2M等蛋白之间有密切的相互作用,发生病理改变时,相互影响也更复杂,导致不同功效中药复方在不同模型上未显示出特异性疗效。但该系统指标可作为评价药物整体疗效的参考指标。
5)对于行为学相关指标而言,不同功效中药复方对两种证型的模型,在8月龄Aβ注射模型的避暗潜伏期、错误次数、错误区时间等指标,及SAMP8模型的水迷宫逃避潜伏期、寻台成功率和避暗潜伏期、错误次数等指标上,表现出了对症药物的优势。提示对症药物对于改善相应证候模型小鼠的空间学习记忆和被动逃避反应能力上有作用,有助于评价不同功效中药复方的药效特点。
总之,这两种拟老年痴呆症小鼠模型在Aβ代谢相关蛋白的表达和行为学上有各自的病理特点,不同功效中药复方对不同模型的起效靶点也有特异性,且对症给药对于改善模型行为学和Aβ生成及降解的环节上,发挥特异性作用,因此这些指标可作为评价不同功效中药复方药效的特异性指标。而LRP1系统的各指标,在两种模型上,未反映出不同功效中药复方的药效特点,作为评价指标,特异性欠佳。所以,对于中药复方药效评价指标而言,应根据药效特点和模型证候进行选择,以期更客观地评价中药复方药效,更准确地发现药物作用靶点和特点。
1. Backgroung
Dementia is a complex disease which be characterized by impairments in cognition and behavior. Behavioural and psychological symptoms of dementia are present in the course of the illness in most patients with dementia. The incidence of dementia among the elderly population is rising rapidly around the world. Due to the numerous cases of patients, there are more and more burden of society, economy and family. Alzheimer's disease(AD) is the leading type of dementia. AD is a neurodegenerative disorder of the aged that has multiple factors, which contribute to AD's etiology in terms of initiation and progression. There are several hypotheses have been formulated to explain this debilitating disease, and those hypotheses often have overlapping features. The best-known hypothesis to explain AD is the Amyloid Cascade Hypothesis which involves the role of the accumulation of amyloid-βpeptide(Aβ) in the brain. Other theories include Dysfunction of Neurovascular Unit which suggests manifold neurovascular pathogenic cascades for AD, cholinergic hypothesis, the role of oxidative stress or neuroinflammation, genes mutation and so on. Current therapeutics on the market, including cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists and productions of modulating Aβmetabolism, provide symptomatic relief but do not alter progression of this disease. Therefore, progress in the areas of prevention and disease modification may be important. Based on Traditongal Chinese medicine, dysfunction of brain, kidney, heart, spleen and liver all may due to AD.Deficiency of kidney essence, asthenia of qi and blood, sputum and blood stasis, internal injury due to seven emotions, prolonged illness consuming healthy qi all would impair the brain. The basic therapeutic methods is Invigorating kidney and supplementing essence, relieve accumulation and resolve stagnation. Traditongal Chinese medical prescriptions are multifunctioning that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD and have a better effection.
This experiment is guided by the pathogenesis theories of Consuming of Kidney Essence and Toxin Hurts Brain Collaterals to study SAMP8(model-P) & hippocampus injection of Aβ1-40 in SAMR1(model-A) models, to compare the actions of Liu Wei Dihuang granule(LWDH) and Tong Luo Jiunao dripping pill(TLJN), and to find the feature of those prescriptions.
2. Objective
1) To test the correlation of aging and cognition impairments in two models;
2) To compare the effect of behavioral test and morphology of two models;
3) To compare the speacil function of two prescriptions, and ascertain the potential drug targets.
3. Methods
1) To investigate the diversity of 2-month-old,6 month-old and 8 month-old SAMP8 and SAMR1 mice using Morris water maze and passive avoidance test(Step-up test).
2) To investigate the discrepancy of 8 month-old model-P and model-A treated by LWDH(PL group & AL group) and TLJN(PT group & AT group) using Morris water maze and passive avoidance test(Step-through test).
3) To compare the difference in all group on expression of Aβ,APP, BACE1, IDE, LRP1, RAGE, apoE and a2M using immunohistochemistry.
4) To compare the difference in all group on level of APP, BACE1, IDE, LRP1, RAGE, apoE and a2M using Weatern blotting.
4. Results
1) To compare with the N group, there are diversity in MWM escape latency, success rate and Step-up test latency, wrong frequency, and Step-though test latency, wrong frequency of 8-month-old model-P and model-A. To compare with the N group, there are diversity in both Step-up test and Step-though test wrong time of model-A. To compare with the N group, there are diversity in MWM swimming speed of model-P.
2) To compare with the A group, there are difference between model-A and model-P on MWM swimming speed, Step-up test wrong frequency, Step-though test wrong frequency, wrong time and expression of APP(cortex), BACE1(cortex), IDE(cortex and hippocampal), LRP1(hippocampal),RAGE(cortex and hippocampal) and apoE(cortex).
3) The irregular expression of Aβ, APP, BACE1, IDE, LRP1, RAGE, apoE and a2M in brains of model-P and model-A. The regulated expression of APP, BACE1, IDE, LRP1 RAGE and apoE were shown in AT group as well as the regulated expression of Aβ, APP, BACE1, IDE, LRP1, RAGE, and a2M were tested in PL group. TLJN have function on model-A by regulated Step-though test latency and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. LWDH have function on model-P by regulated MWM success rate, Step-though test latency and expression of Aβ,APP, BACE1, IDE and RAGE.
5. Conclusions
1) There are correlation of aging and cognition impairments in two models;
2) Model-P and model-A have severely impaired acquisition and retention of spatial learning task and passive avoidance response, and neurochemical. So SAMP8 maybe a more severely model.
3) These two traditongal Chinese medical prescriptions have significant effection, due to selecting of treatment based on the differential diagnosis. The expreesion of APP、BACE1、IDE coule be useful develop and evaluate potential new formulations.
4) There are few difference between LWDH and TLJN in clearance of Aβby LRP1 system. So the evaluation for traditongal Chinese medical prescriptions should be unambiguous.
5) The behavioral test maybe unsuitable as a evaluation for different traditongal Chinese medical prescriptions
In conclusion, SAMP8 and hippocampus injection of Aβ1-40 in SAMR1 mice have difference on MWM swimming speed, Step-up test wrong frequency, Step-though test wrong frequency, wrong time and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. To hippocampus injection of Aβ1-40 in SAMR1 mice, TLJN have function by regulated Step-though test latency, and expression of APP, BACE1, IDE, LRP1,RAGE and apoE. On the other hand, to SAMP8 mice LWDH have function by regulated MWM success rate, Step-though test latency and expression of Aβ, APP, BACE1, IDE and RAGE. These two models and two traditongal Chinese medical prescriptions have their own characteristics.
引文
[1]Christian Humpel.Chronic mild cerebrovascular dysfunction as a cause for Alzheimer's disease[J]? Exp Gerontol,2011,46(4):225-232.
[2]K.Maurer.Historical background of Alzheimer's research done 100 years ago[J].J Neural Transm,2006,113:1597-1601.
[3]Nelson PT,Head E,Schmitt FA,et al.Alzheimer's disease is not "brain aging" neuropathological,genetic,and epidemiological human studies[J].Acta Neuropathol,2011,121(5):571-587.
[4]Grand JH,Caspar S,Macdonald SW.Clinical features and multidisciplinary approaches to dementia care[J].J Multidiscip Healthc,2011,4:125-147.
[5]Hellstrom-Lindahl E,Viitanen M,Marutle A.Comparison of Abeta levels in the brain of familial and sporadic Alzheimer's disease[J].Neurochem Int, 2009,55(4):243-252.
[6]Janicki SC,Schupf N.Hormonal influences on cognition and risk for Alzheimer's disease[J].Curr Neurol Neurosci Rep,2010,10(5):359-366.
[7]Mehta KM,Stewart AL,Langa KM,et al."Below average" self-assessed school performance and Alzheimer's disease in the Aging,Demographics,and Memory Study[J].Alzheimers Dement,2009,5(5):380-387.
[8]Beeri MS,Goldbourt U.Late-life dementia predicts mortality beyond established midlife risk factors[J].Am J Geriatr Psychiatry,2011,19(1):79-87.
[9]Santibanez M,Bolumar F,Garcia AM.Occupational risk factors in Alzheimer's disease:a review assessing the quality of published epidemiological studies[J].Occup Environ Med,2007,64(11):723-732.
[10]Chen JH,Lin KP,Chen YC.Risk Factors for Dementia[J].J Formos Med Assoc, 2009,108(10):754-764.
[11]Neafsey EJ,Collins MA.Moderate alcohol consumption and cognitive risk[J].Neuropsychiatr Dis Treat,2011,7:465-484.
[12]Ciobica A,Padurariu M.Bild W,et al.Cardiovascular risk factors as potential markers for mild cognitive impairment and Alzheimer's disease[J].Psychiatr Danub,2011,23(4):340-346.
[13]Reitz C.Tang MX,Schupf N,et al.Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease[J].Arch Neurol,2010,67(12):1491-1497.
[14]Schrijvers EM,Witteman JC,Sijbrands EJ,et al.Insulin metabolism and the risk of Alzheimer disease:the Rotterdam Study[J].Neurology,2010, 75(22):1982-1987.
[15]Doherty GH.Obesity and the ageing brain:could leptin play a role in neurodegeneration[J]? Curr Gerontol Geriatr Res,2011,2011:708154.
[16]Flirski M,Sobow T,Kloszewska I.Behavioural genetics of Alzheimer's disease: a comprehensive review[J].Arch Med Sci,2011,7(2):195-210.
[17]Lopez OL.The growing burden of Alzheimer's disease[J].Am J Manag Care, 2011,13:S339-345.
[18]R.A.Armstrong.The Pathogenesis of Alzheimer's Disease:A Reevaluation of the Amyloid Cascade Hypothesis[J].Int J Alzheimers Dis,2011,Feb 7:1-6.
[19]Michael S Wolfe,Suzanne Y Guenette.APP at a glance[J].J Cell Sci,2007,120(18):3157-3161.
[20]O'Brien RJ,Wong PC.Amyloid Precursor Protein Processing and Alzheimer's Disease[J].Annu Rev Neurosci,2011,34:185-204.
[21]Hui Zheng,Edward H Koo.Biology and pathophysiology of the amyloid precursor protein[J].Mol.Neurodegener,2011,6(1):27-42.
[22]Thinakaran G,Koo EH.Amyloid precursor protein trafficking,processing,and function[J].J Biol Chem,2008,283(44):29615-29619.
[23]Alessandro Biffi,Steven M.Greenberg.Cerebral amyloid angiopathy:A systematic review[J].J Clin Neurol 2011;7:1-9.
[24]Gouras GK,Tampellini D,Takahashi RH,et al.Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease[J].Acta Neuropathol, 2010,119(5):523-541.
[25]Pleckaityte M.Alzheimer's disease:a molecular mechanism,new hypotheses,and therapeutic strategies[J].Medicina (Kaunas),2010,46(1):70-76.
[26]Hernandez F,de Barreda EG,Fuster-Matanzo A,et al.The role of GSK3 in Alzheimer disease[J].Brain Res Bull,2009,80(4-5):248-250.
[27]Parihar MS,Brewer GJ.Amyloid Beta as a Modulator of Synaptic Plasticity[J].J Alzheimers Dis,2010,22(3):741-763.
[28]Struble RG,Ala T.Patrylo PR,et al.Is brain amyloid production a cause or a result of dementia of the Alzheimer's type[J]? J Alzheimers Dis, 2010,22(2):393-399.
[29]Gregory A.Elder,Miguel A.Gama Sosa,Rita De Gasperi.Transgenic Mouse Models of Alzheimer's Disease[J].Mt Sinai J Med,2010,77(1):69-81.
[30]Shuko Takeda,Naoyuki Sato,Kazue Niisato,et al.Validation of Aβ1-40 administration into mouse cerebroventricles as an animal model for Alzheimer disease[J].Brain research.2009,1280:137-147.
[31]Perluigi M,Butterfield DA.Oxidative Stress and Down Syndrome:A Route toward Alzheimer-Like Dementia[J].Curr Gerontol Geriatr Res, 2012,2012:724904.
[32]De Meyer G,Shapiro F,Vanderstichele H,et al.Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people[J].Arch Neurol,2010,67(8):949-956.
[33]Kaddurah-Daouk R,Rozen S,Matson W,et al.Metabolomic changes in autopsy-confirmed Alzheimer's disease[J].Alzheimers Dement,2011, 7(3):309-317.
[34]Mary Griffin Krone,Andrij Baumketner,Summer L.Bernstein,et al.Effects of familial mutations on the folding nucleation of the Alzheimer Amyloid β-protein[J].J Mol Biol,2008,381(1):221-228.
[35]Nation DA,Hong S,Jak AJ.Stress,exercise,and Alzheimer's disease:A neurovascular pathway[J].Med Hypotheses,2011,76(6):847-854.
[36]Berislav V.Zlokovic.Neurovascular mechanisms of Alzheimer's neurodegeneration[J].Neurosciences.2005,April,28(4):202-208.
[37]Zlokovic BV.The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders[J].Neuron,2008,57(2):178-201.
[38]Smith EE,Greenberg SM.Beta-amyloid,blood vessels,and brain function[J]. Stroke,2009,40(7):2601-2606.
[39]Grammas P.Neurovascular dysfunction,inflammation and endothelial activation:Implications for the pathogenesis of Alzheimer's disease[J].J Neuroinflammation,2011,8:26.
[40]Matsunari I,Samuraki M,Chen WP,et al.Comparison of 18F-FDG PET and optimized voxel-based morphometry for detection of Alzheimer's disease:aging effect on diagnostic performance[J].J Nucl Med,2007,48(12):1961-1970.
[41]Kumar-Singh S.Cerebral amyloid angiopathy:pathogenetic mechanisms and link to dense amyloid plaques[J].Genes Brain Behav,2008,1:67-82.
[42]Grinberg LT,Thal DR.Vascular pathology in the aged human brain[J].Acta Neuropathol,2010,119:277-290.
[43]Rashid Deane,Zhenhua Wu,Berislav V.Zlokovic.RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier[J].Stroke.2004,35:2628-2631.
[44]Sagare A,Deane R,Bell RD,et al.Clearance of amyloid-beta by circulating lipoprotein receptors[J].Nat Med.2007,13(9):1029-1031.
[45]R.E.Tanzi,R.D.Moir,S.L.Wagner.Clearance of Alzheimer's Aβ peptide:the many roads to perdition[J].Neuron,2004,43:605-608.
[46]Shibata M,Yamada S,Kumar SR,et al.Clearance of Alzheimer's amyloid-β(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier[J].J Clin Invest,2000,106(12):1489-1499.
[47]R Deane,RD Bell,A Sagare,et al.Clearance of amyloid-β peptide across the blood-brain barrier:implication for therapies in Alzheimer's disease[J].CNS Neurol Disord Drug Targets,2009,8(1):16-30.
[48]R.Deane,A.Sagare,B.Zlokovic.The Role of the Cell Surface LRP and Soluble LRP in Blood-Brain Barrier Ap Clearance in Alzheimer's Disease[J].Curr Pharm Des,2008,14(16):1601-1605.
[49]Milan Fiala,Robert Veerhuis.Biomarkers of inflammation and amyloid-β phagocytosis in patients at risk of Alzheimer disease[J].Exp Gerontol,2010,45(1): 57-63.
[50]Pantoni L,Gorelick P.Advances in Vascular Cognitive Impairment 2010[J].Stroke,2011,42:291-293.
[51]Kalaria RN,Maestre GE,Arizaga R,et al.Alzheimer's disease and vascular dementia in developing countries:prevalence,management,and risk factors[J].Lancet Neurol,2008,7(9):812-826.
[52]Robert D.Bell1,Berislav V.Zlokovic.Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease[J].Acta Neuropathol. 2009,118(1):103-113.
[53]Franceschi C,Valensin S.Bonafe M,et al.The network and the remodeling theories of aging:historical background and new perspectives[J].Exp Gerontol,2000,35(6-7):879-896.
[54]Hickman SE,Allison EK,Khoury JE.Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice[J].J Neurosci,2008,28(33):8354-8360.
[55]JJ Rodriguez,J Witton,M Olabarria,et al.Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease[J].Cell Death Dis,2010,1:1-6.
[56]Saez TE,Pehar M,Vargas M,et al.Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons[J].In Vivo,2004,18(3):275-280.
[57]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis[J].Science,1992,256(5054):184-185.
[58]Butterfield DA,Reed T,Newman SF.et al.Roles of Amyloid β-Peptide-Associated Oxidative Stress and Brain Protein Modifications in the Pathogenesis of Alzheimer's Disease and Mild Cognitive Impairment[J].Free Radic Biol Med,2007,43(5):658-677.
[59]Axelsen PH,Komatsu H,Murray Ⅳ.Oxidative Stress and Cell Membranes in the Pathogenesis of Alzheimer's Disease[J].Physiology (Bethesda), 2011,26(1):54-69.
[60]Atri A.Effective pharmacological management of Alzheimer's disease[J].Am J Manag Care,2011,13:S346-355.
[61]Rodrigo O.Kuljis.Integrative understanding of emergent brain properties,quantum brain hypotheses,and connectome alterations in dementia are key challenges to conquer Alzheimer's disease[J].Front Neurol,2010,26:1-15.
[62]Wang S,Wang R,Chen L,et al.Expression and functional profiling of neprilysin,insulin degrading enzyme and endothelin converting enzyme in prospectively studied elderly and Alzheimer's brain[J].J Neurochem,2010,115(1): 47-57.
[63]Numata K,Kaplan DL.Mechanisms of Enzymatic Degradation of Amyloid Beta Microfibrils Generating Nanofilaments and Nanospheres Related to Cytotoxicity[J].Biochemistry,2010,49(15):3254-3260.
[64]Luchsinger JA,Gustafson DR.Adiposity,type 2 diabetes,and Alzheimer's disease[J].J Alzheimers Dis,2009,16(4):693-704.
[65]Cheng D,Noble J,Tang MX,et al.Type 2 diabetes and late-onset Alzheimer's disease[J].Dement Geriatr Cogn Disord,2011,31 (6):424-430.
[66]Bezprozvanny I,Mattson MP.Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease[J].Trends Neurosci,2008,31 (9):454-463.
[67]Kawahara M,Kato-Negishi M.Link between Aluminum and the Pathogenesis of Alzheimer's Disease:The Integration of the Aluminum and Amyloid Cascade Hypotheses[J].Int J Alzheimers Dis,2011,2011:276393.
[68]Strozyk D,Launer LJ,Adlard PA,et al.Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid[J].Neurobiol Aging, 2009,30(7):1069-1077.
[69]Beel AJ,Sakakura M,Barrett PJ,et al.Direct Binding of Cholesterol to the Amyloid Precursor Protein:An Important Interaction in Lipid-Alzheimer's Disease Relationships[J]? Biochim Biophys Acta,2010,1801(8):975-982.
[70]Russell H.Swerdlow,Jeffrey M.Burns,Shaharyar M.Khan.The Alzheimer's Disease Mitochondrial Cascade Hypothesis[J].J Alzheimers Dis,2010,20(Suppl 2):265-279.
[71]Escames G,Lopez A,Garcia JA,et al.The Role of Mitochondria in Brain Aging and the Effects of Melatonin[J].Curr Neuropharmacol,2010,8(3):182-193.
[72]Selkoe DJ.Alzheimer's disease is a synaptic failure[J]. Science,2002, 298(5594):789-791.
[73]Ondrejcak T,Klyubin I,Hu NW,et al.Alzheimer's disease amyloid beta-protein and synaptic function[J].Neuromolecular Med,2010,12(1):13-26.
[74]Bekris LM,Yu CE,Bird TD,et al.Genetics of Alzheimer Disease[J].J Geriatr Psychiatry Neurol,2010,23(4):213-227.
[75]Ertekin-Taner N.Genetics of Alzheimer's Disease:A Centennial Review[J].Neurol Clin,2007,25(3):611-v.
[76]DeMichele-Sweet MA,Sweet RA.Genetics of Psychosis in Alzheimer Disease: A Review[J].J Alzheimers Dis,2010,19(3):761-780.
[77]Pimplikar SW,Nixon RA,Robakis NK,et al.Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis[J].J Neurosci, 2010,30(45):14946-14954.
[78]Mayeux R,Reitz C,Brickman AM.et al.Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment—Part 1[J]. Alzheimers Dement.2011,7(1):15-34.
[79]Seshadri S,Beiser A,Au R,et al.Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment—Part 2[J]. Alzheimers Dement,2011,7(1):35-52.
[80]Jicha GA,Abner EL,Schmitt FA,et al.Preclinical AD Workgroup staging: pathological correlates and potential challenges[J].Neurobiol Aging,2012, 33(3):622.el-622.e16.
[81]Cumming JL.Biomarkers in Alzheimer's disease drug development[J]. Alzheimers Dement,2011,7(3):e13-44.
[82]Sperling RA,Aisen PS,Beckett LA,et al.Toward defining the preclinical stages of Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):280-292.
[83]Forlenza OV,Diniz BS,Gattaz WF.Diagnosis and biomarkers of predementia in Alzheimer's disease[J].BMC Med,2010,8:89.
[84]Albert MS,DeKosky ST,Dickson D,et al.The diagnosis of mild cognitive impairment due to Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):270-279.
[85]Jack CR Jr,Barkhof F,Bernstein MA,et al.Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease[J].Alzheimers Dement, 2011,7(4):474-485.e4.
[86]Riverol M,Lopez OL.Biomarkers in Alzheimer's disease[J].Front Neurol, 2011,2:46.
[87]Alzheimer's Association,Thies W,Bleiler L.2011 Alzheimer's disease facts and figures[J].Alzheimers Dement,2011,7(2):208-244.
[88]Seyfried LS,Kales HC,Ignacio RV,et al.Predictors of suicide in patients with dementia[J].Alzheimers Dement,2011,7(6):567-573.
[89]Jack CR Jr,Albert MS,Knopman DS,et al.Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):257-262.
[90]McKhann GM,Knopman DS,Chertkow H,et al.The diagnosis of dementia due to Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011 May;7(3):263-269.
[91]Demarin V,Zavoreo I,Kes VB,et al.Biomarkers in Alzheimer's disease[J].Clin Chem Lab Med,2011,49(5):773-778.
[92]Griffiths HH,Morten IJ,Hooper NM.Emerging and potential therapies for Alzheimer's disease[J].Expert Opin Ther Targets,2008,12(6):693-704.
[93]Sarah L Cole,Robert Vassar.The Alzheimer's disease beta-secretase enzyme,BACE1 [J].Molecular Neurodegeneration 2007,2:22.
[94]Huilin Li,Michael S.Wolfe,Dennis J.Selkoe.Toward structural elucidation of the y-secretase complex[J].Structure,2009,17(3):326-334.
[95]Tomita T,Wong PC.Selectivity to amyloid-β precursor protein cleavage provides hope against Alzheimer's[J].Alzheimers Res Ther,2011,3(2):7.
[96]Sastre M,Walter J,Gentleman SM.Interactions between APP secretases and inflammatory mediators[J].J Neuroinflammation,2008,5:25.
[97]Weinmann S,Roll S,Schwarzbach C,et al.Effects of Ginkgo biloba in dementia:systematic review and meta-analysis[J].B M C Geriatr,2010,10:14.
[98]Daniel Hafez,Jeffrey Y.Huang,Alexis M.Huynh,et al.Neprilysin-2 Is an Important β-Amyloid Degrading Enzyme[J].Am J Pathol,2011,178(1):306-312.
[99]Carrasquillo MM,Belbin O,Zou F.et al.Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA,Aβ,and Alzheimer's Disease[J].PLoS ONE,2010,5(1):e8764.
[100]Amijee H,Scopes DI.The Quest for Small Molecules as Amyloid Inhibiting Therapies for Alzheimer's Disease[J].J Alzheimers Dis,2009,17(1):33-47.
[101]Creed MC,Milgram NW.Amyloid-modifying therapies for Alzheimer's disease:therapeutic progress and its implications[J].Age (Dordr),2010,32(3):365-384.
[102]Salloway S,Sperling R,Keren R,et al.A phase 2 randomized trial of ELND005,scyllo-inositol,in mild to moderate Alzheimer disease[J]. Neurology, 2011,77(13):1253-1262.
[103]Fu HJ,Liu B,Frost JL,et al.Amyloid-β Immunotherapy for Alzheimer's Disease[J].CNS Neurol Disord Drug Targets,2010,9(2):197-206.
[104]Town T.Alternative Aβ Immunotherapy Approaches for Alzheimer's Disease[J].CNS Neurol Disord Drug Targets,2009,8(2):114-127.
[105]McClendon MJ,Hernandez S,Smyth KA,et al.Memantine and acetylcholinesterase inhibitor treatment in cases of CDR 0.5 or questionable impairment[J].J Alzheimers Dis.2009,16(3):577-583.
[106]Hansen RA,Gartlehner G,Webb AP,et al.Efficacy and safety of donepezil,galantamine,and rivastigmine for the treatment of Alzheimer's disease:a systematic review and meta-analysis[J].Clin Interv Aging,2008,3(2):211-225.
[107]Lockhart IA,Orme ME,Mitchell SA.The Efficacy of Licensed-Indication Use of Donepezil and Memantine Monotherapies for Treating Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer's Disease: Systematic Review and Meta-Analysis[J].Dement Geriatr Cogn Dis Extra, 2011,1(1):212-227.
[108]Pohanka M.Cholinesterases,a target of pharmacology and toxicology[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2011,155(3):219-229.
[109]Thomas SJ,Grossberg GT.Memantine:a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias[J].Clin Interv Aging,2009,4:367-377.
[110]Anekonda TS,Quinn JF,Harris C,et al.L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease[J].Neurobiol Dis,2011,41(1):62-70.
[111]Srinivasan V,Spence DW,Pandi-Perumal SR,et al.Melatonin in mitochondrial dysfunction and related disorders[J].Int J Alzheimers Dis, 2011,2011:326320.
[112]Iqbal K,Liu F,Gong CX,et al.Tau in Alzheimer disease and related tauopathies[J].Curr Alzheimer Res,2010,7(8):656-664.
[113]Bush AI,Tanzi RE.Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis[J].Neurotherapeutics,2008,5(3):421-432.
[114]Zotova E,Nicoll JA,Kalaria R,et al.Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy[J].Alzheimers Res Ther,2010,2(1):1.
[115]Davies P,Koppel J.Mechanism-based treatments for Alzheimer's disease[J].Dialogues Clin Neurosci,2009,11 (2):159-169.
[116]Thoonsen H,Richard E,Bentham P,et al.Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage:cause for concern[J]? Stroke, 2010,41 (11):2690-2692.
[117]Sergio A.Rosales-Corral,Dario Acuna-Castroviejo,Ana CotoMontes,et al.Alzheimer's disease:pathological mechanisms and the beneficial role of melatonin[J].J.Pineal Res,2011,52(2):167-202.
[118]Stone JG,Casadesus G,Gustaw-Rothenberg K,et al.Frontiers in Alzheimer's Disease Therapeutics[J].Ther Adv Chronic Dis,2011,2(1):9-23.
[119]Ryan J,Scali J,Carriere I,et al.Hormonal treatment,mild cognitive impairment and Alzheimer's Disease[J].Int Psychogeriatr,2008,20(1):47-56.
[1]沈自尹,黄建华,林伟,等.从整体论到系统生物学进行肾虚和衰老的研究[J].中国中西医结合杂志,2009,6(6)：548-550.
[2]刘宁,郭蕾.阿尔茨海默病中医认识[J].中华中医药学刊,2011,29(6)：1254-1255.
[3]卿照前.六味地黄丸延缓老年痴呆症50例疗效观察[J].中国中医药科技,2007,5：75-76.
[4]王迪,尚晓玲.六味地黄丸防治老年病[J].中国老年学杂志,2011,3：161-164.
[5]张伟伟,刘银辉,孙启新.六味地黄丸对老年大鼠神经系统的抗衰老作用[J].陕西中医,2010,31(9)：1264-1265.
[6]易健,刘柏炎,蔡光先.超微六味地黄汤对老年痴呆大鼠认知功能和脑组织碱性成纤维生长因子表达的影响[J].中国实验方剂学杂志,2011,21：149-152.
[7]Zhang WW,Sun QX,Liu YH,et al.Chronic administration of Liu Wei Dihuang protects rat's brain against D-galactose-induced impairment of cholinergic system[J].Sheng Li Xue Bao,2011,63(3):245-255.
[8]Lee KS,Lim BV,Chang HK,et al.Liuweidihuang-tang improves spatial memory function and increases neurogenesis in the dentate gyrus in rats[J].Fitoterapia, 2005,76(6):514-519.
[9]Wu CR,Lin LW,Wang WH,et al. The ameliorating effects of LiuWei Dihuang Wang on cycloheximide-induced impairment of passive avoidance performance in rats[J]. J Ethnopharmacol,2007,113(1):79-84.
[10]冯炯,臧敏.六味地黄丸对痴呆模型小鼠学习记忆及细胞因子的影响[J].山东中医杂志,2010,4：50-51.
[11]刘继平,兰洲,傅强,等.六味地黄醇提水洗脱部位对D-半乳糖所致小鼠衰老模型的影响[J].药学与临床研究,2011,3：40-43.
[12]富宏,王学美,刘庚信,等.加味五子衍宗颗粒对轻度认知功能障碍患者记忆功能及血清β淀粉样蛋白的影响[J].中国老年学杂志,2007,8：15-17.
[13]黎巍威,王学美.中医从“肾”防治阿尔茨海默病的现代研究[J].中国实验方剂学杂志,2010,16(13)：227-230.
[14]褚松龄,王学美,富宏,等.加味五子衍宗方及有效组分对记忆障碍小鼠中枢胆碱能系统的影响[J].中国中医药信息杂志,2006,2：21-22.
[15]王建明.七福饮加味治疗老年性痴呆32例[J].辽宁中医杂志,2002,1：45.
[16]兴桂华,林春荣,张晓杰,等.七福饮对Aβ1-42诱导老年性痴呆模型大鼠海马 神经细胞凋亡的保护作用[J].中国实验方剂学杂志,2010,12：146-149.
[17]王玉宇.左归饮加减治疗老年性痴呆60例[J].海南医学,2001,2：40-41.
[18]王燕.左归饮对衰老模型小鼠血清SOD GSH-Px MDA及IL-2的影响[J].中华中医药学刊,2009,7：160-161.
[19]李枝朝.地黄饮子治疗老年痴呆症18例[J].四川中医,2011,2：93.
[20]李凌云.地黄饮子在老年脑病中的临床应用[J].中国民间疗法,2010,6：35.
[21]牛英才,董妙先,兴桂华,等.Ap损伤后大鼠SOD和MDA的变化及补肾活血化痰法的干预作用[J].中华中医药学刊,2008,(1)：75-77.
[22]谢宁,牛英才,宋琳,等.加减地黄饮子对Aβ-40所致痴呆大鼠学习记忆、脑酶活性的影响[J].中医药信息,2004,2：60-61.
[23]陈岩,袁勇.活脑方治疗阿尔茨海默病肾虚髓减证临床研究[J].山东医药,2008,32：87-88.
[24]王树炜,金秀梅.益智醒脑汤治疗老年性痴呆50例[J].四川中医,2005,5：51.
[25]夏宗勤,胡雅儿,张永芳,等.一些重要滋肾阴中药防治神经退行性病变的分子机理[C].中国核科学技术进展报告——中国核学会2009年学术年会论文集,2009,11：36-41.
[26]徐进友.从风痰瘀论治老年性痴呆[J].辽宁中医药大学学报.2012,2：168-169.
[27]贾怡蓓,白雪,张宇红,等.从瘀辨治不同法则治疗Alzheimer病疗效的临床观察[J].中西医结合心脑血管病杂志,2010,8(1)：37-39.
[28]武宏.通窍活血汤加减治疗血管性痴呆40例[J].陕西中医,2006,11：29-30.
[29]Liu CZ,Zhou LH,Shui Z,et al.Clinical Observation Tongqiao Huoxue Tang and Buyang Huanwu Tang for Treatment of Vascular Dementia—A report of 36 Cases[J].Journal of Traditional Chinese Medicine,2003,4:5-7.
[30]葛朝亮,汪宁.通窍活血汤对血管性痴呆大鼠脑皮质中NO、ET-1、LPO含量的实验研究[J].安徽医药,2011,9：11-13.
[31]陈建鸿,杜建.益气解毒法治疗老年性痴呆的临床研究[J].福建中医学院学报,2006,5：9-10.
[32]邱昕,陈国华,冯佩,等.黄连解毒汤对APP/PS1双转基因AD小鼠海马区病理形态学及脑内β-APP基因mRNA的影响[J].神经损伤与功能重建,2010,5(6)：404-408.
[33]宋建芳,边宝林,王宏洁.黄连解毒汤治疗老年性痴呆药理研究进展[J].中国中医药信息杂志,2010,：17(5)：110-112.
[34]张晓杰.大鼠脑内注射Aβ1-40致海马损伤的炎症相关机制及通络救脑口 服液的作用[D].北京中医药大学,2008,2.
[35]张晓杰,牛英才,周丽,等.海马注射β-淀粉样蛋白对BACE1 mRNA的影响及通络救脑口服液的干预作用[J].中药药理与临床,2006,6：52-55.
[36]张晓杰,董海影,孙玉荣,等.大鼠大脑海马注射β-淀粉样蛋白对caspsae-3蛋白表达的影响及通络救脑口服液的干预作用[J].中华中医药杂志,2010,10：144-146.
[37]张晓杰,张静艳,赵坤,等.通络救脑口服液对AD大鼠海马单胺氧化酶活性、脂褐素含量的影响[J].中国老年学杂志,2010,18：78-80.
[38]张晓杰,董海影,李澎涛.通络救脑口服液对AD大鼠学习记忆能力及突触素蛋白表达的影响[J].北京中医药大学学报,2010,7：49-54.
[39]兴桂华,牛英才,张晓杰,等.通络救脑口服液对老年性痴呆模型大鼠海马区生长抑素、胆碱乙酰化酶表达的影响[J].中华中医药杂志,2008,4：96-98.
[40]董海影,张春庆,宫国良,等.通络救脑口服液对AD大鼠学习记忆能力及nNOS、SS表达的影响[J].时珍国医国药,2010,10：126-128.
[41]张晓杰,张春庆,胡南,等.Aβ1-40脑内注射对大鼠海马超氧化物歧化酶丙二醛的影响及通络救脑口服液的干预作用[J].时珍国医国药,2010,7：86-87.
[42]李小靓.通络救脑注射液对大鼠海马神经元的保护作用[D].北京中医药大学,2009,10.
[43]顾兆伟.通络救脑注射液治疗中风病(风火上扰、瘀血阻络证)的临床研究[D].长春中医药大学,2008,4.
[44]Rafii MS,Walsh S,Little JT,et al.A phase Ⅱ trial of huperzine A in mild to moderate Alzheimer disease[J].Neurology,2011,76(16):1389-1394.
[45]Pohanka M.Cholinesterases,a target of pharmacology and toxicology[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2011,155(3):219-229.
[46]Park P,Schachter S,Yaksh T.Intrathecal huperzine A increases thermal escape latency and decreases flinching behavior in the formalin test in rats[J].Neurosci Lett,2010,470(1):6-9.
[47]Zhang GR,Cheng XR,Zhou WX,et al.Age-related expression of calcium/calmodulin-dependent protein kinase Ⅱ A in the hippocampus and cerebral cortex of senescence accelerated mouse prone/8 mice is modulated by anti-Alzheimer's disease drugs[J].Neuroscience,2009,159(1):308-315.
[48]Shi J,Liu Q,Wang Y,et al.Coadministration of huperzine A and ligustrazine phosphate effectively reverses scopolamine-induced amnesia in rats[J].Pharmacol Biochem Behav,2010,96(4):449-453.
[49]Zoladz PR,Diamond DM.Linear and non-linear dose-response functions reveal a hormetic relationship between stress and learning[J].Dose Response, 2008,7(2):132-148.
[50]Hemendinger RA,Armstrong EJ 3rd,Persinski R,et al.Huperzine A provides neuroprotection against several cell death inducers using in vitro model systems of motor neuron cell death[J].Neurotox Res,2008,13(1):49-61.
[51]Park H,Oh MS.Houttuyniae Herba protects rat primary cortical cells from Aβ25-35-induced neurotoxicity via regulation of calcium influx and mitochondria-mediated apoptosis[J].Hum Exp Toxicol,2012 Jan 19.
[52]Eiden M,Leidel F,Strohmeier B,et al.A Medicinal Herb Scutellaria lateriflora Inhibits PrP Replication in vitro and Delays the Onset of Prion Disease in Mice[J].Front Psychiatry,2012,3:9.
[53]Xian YF,Lin ZX,Zhao M,et al.Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice[J].Planta Med,2011,77(18):1977-1983.
[54]Mei Z,Yan P,Situ B,et al.Cryptotanshinione Inhibits (3-Amyloid Aggregation and Protects Damage from (3-Amyloid in SH-SY5Y Cells[J].Neurochem Res, 2012,37(3):622-628.
[55]da Rocha MD,Viegas FP,Campos HC,et al.The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders Ⅱ:Alzheimer's disease[J].CNS Neurol Disord Drug Targets,2011,10(2):251-270.
[56]苏芮,韩振蕴,范吉平.阿尔茨海默病中医病因病机探讨[J].中华中医药杂志,2010,25(5)：743-744.
[57]贾树林.加减洗心汤治疗血管性痴呆30例临床观察[J].长春中医药大学学报,2011,3：90-91.
[58]赵建军.补肾健脾法治疗脑萎缩68例临床观察[J].中国现代药物应用,2007,8：52.
[59]郑丽,翟李娟.辨证分型治疗老年痴呆症30例疗效观察[J].河南中医学院学报.2004,4：54-55.
[60]吴虹.浅谈中医对老年性痴呆症的认识和防治[J].现代中西医结合杂志.2000,17：74-75.
[61]胡梅芳.老年性痴呆从肾虚痰瘀论治[J].浙江中医药大学学报,2009,33(3)：375-376.
[62]刘玲,董欢,姜幼明,等.涤痰汤对小鼠学习记忆功能障碍的影响[J].光明中医,2010,8：52-55.
[63]芦凤琴,闫伟.加味二陈汤治疗脑卒中后血管性痴呆40例[J].中国中医急症,2011,4：131-132.
[64]曹玉笈,刘珍华.益气活血化痰法治疗老年性痴呆症36例[J].国医论坛,2004,3：34.
[65]王辉,韩涛,张婷,等.化痰祛瘀治疗血管性认知功能障碍随机对照试验的Meta分析[J].中国实验方剂学杂志,2012,3：267-270.
[66]孔令海,孙金华.癫狂梦醒汤加减治疗老年性痴呆50例[J].中国医药导报,2009,16：137.
[67]张晶,张彪.还少丹加减治疗血管性痴呆54例[J].南京中医药大学学报,2008,6：70-71.
[68]张峰,贺林,朱晨,等.还少丹加减治疗血管性痴呆60例[J].光明中医,2011,8：72-73.
[69]龚梦娟,邹忠杰,谢媛媛.还少丹对记忆障碍模型小鼠空间学习记忆能力的影响[J].时珍国医国药,2011,8：114-115.
[70]李杰.金匮肾气丸加减治疗老年性痴呆的临床观察[J].中国医药指南,2010,29：272-273.
[71]赵振,赵力维.金匮肾气丸加味治疗老年轻度认知功能障碍临床观察[J].吉林中医药,2009,7：35-36.
[72]何慧,张玉莲,崔远武,等.老年性痴呆中医治则治法规律研究[J].吉林中医药,2012,2：23-25.
[73]Sun M,Zhou T,Zhou L,et al.Formononetin Protects Neurons Against Hypoxia-Induced Cytotoxicity Through Upregulation of ADAM10 and sApPPa[J].J Alzheimers Dis,2012,28(4):795-808.
[74]魏永吾,王红.辩证治疗老年痴呆50例[J].陕西中医,2009,7：53-54.
[75]田旭升,安平.左归丸对痴呆鼠氧化反应及细胞凋亡的影响[J].时珍国医国药,2007,12：65-66.
[76]徐光华.补肝肾活血通窍中药治疗老年性痴呆40例疗效观察[J].医学信息,2010,5：239-240.
[77]卢昕,芦霜,陈民.用“补肾祛痰化瘀”法辨证施护老年痴呆的研究[J].中华中医药学刊,2009,5：120-121.
[78]于晓宁.补肾活血化痰法治疗老年性痴呆42例临床观察[J].中医药导报,2006,2：32-33.
[79]Yang DY,Wang XZ.Gu Sui Bu(Rhizoma Drynariae)—A Good Drug for Senile Dementia[J].Journal of Traditional Chinese Medicine,2005,4:52-53.
[80]黄启辉,魏昌秀.李庆明教授对老年痴呆病因病机的认识及其辨证分型[J].中医药学刊,2003,21(5)：647.
[81]胡九东,王嘉敏.补肾泻浊治疗老年性痴呆30例[J].中国临床医生,1999,2：49.
[82]胡慧,王平,孔明望,等.补肾化痰方药对阿尔茨海默病模型大鼠脑组织钙/钙调素依赖的蛋白激酶Ⅱ-α活性的影响[J].中华中医药杂志,2010,25(5)：149-151.
[83]梅静,刘春光,孙利.针灸治疗老年性痴呆76例[J].中国民间疗法,2003,11(12)：14-15.
[84]吴迪.针灸治疗早老性痴呆36例[J].四川中医,2004,3：94-95.
[85]董洪涛,白英.针刺疗法对老年性痴呆患者MMSE量表得分的影响.中医外治杂志,2002,11(3)：6-7.
[86]唐勇,余曙光,陈瑾,等.针刺对老年性痴呆认知功能及AChE的影响.上海针灸杂志,2001,20(3)：6-7.
[87]戴思思,董克礼,朱宏.“补肾活血”针刺法对老年性痴呆模型SAMP8小鼠学习记忆能力和脑组织AChE活性的影响[J].上海针灸杂志,2010,29(1)：57-59.
[88]杨定荣,彭力,穆敬平,等.针刺结合穴位注射治疗老年痴呆临床观察[J].中国康复理论与实践,2008,14(1)：81.
[89]马梅青.安神醒脑汤配合针灸治疗老年性痴呆56例[J].陕西中医,2003,8：30-31.
[90]Ho YS,So KF,Chang RC.Drug discovery from Chinese medicine against neurodegeneration in Alzheimer's and vascular dementia[J].Chin Med,2011,6:15.
[1]Debby Van Dam,Peter Paul De Deyn. Drug discovery in dementia:the role of rodent models[J].Nat Rev Drug Discov,2006,Nov;5(11):956-970.
[2]Toshio Takeda.Senescence-accelerated mouse (SAM) with special references to neurodegeneration models,SAMP8 and SAMP10 mice[J].Neurochem Res,2009, 34:639-659.
[3]Koji Tomobe,Yasuyuki Nomura.Neurochemistry,neuropathology,and heredity in SAMP8:A mouse model of senescence[J].Neurochem Res,2009,34:660-669.
[4]Yasunobu Okuma,Yasuyuki Nomura.Senescence-accelerated mouse (SAM) as an animal model of senile dementia:pharmacological,neurochemical and molecular biological approach[J].Jpn.J.Pharmacol,1998,78:399-404.
[5]Kumar VB,Franko M,Banks WA,et al.Increase in Presenilin 1(PS1) levels in senescence-accelerated mice(SAMP8) may indirectly impair memory by affecting amyloid precursor protein(APP) processing[J].J Experimental Biology,2009, 212:494-498.
[6]Kim BH,Meeker HC,Shin HY,et al.Physiological properties of astroglial cell lines derived from mice with high (SAMP8) and low (SAMR1,ICR) levels of endogenous retro virus [J].Retro virology,2008,5:104.
[7]Pang KC,Miller JP,Fortress A,et al.Age-related disruptions of circadian rhythm and memory in the senescence-accelerated mouse (SAMP8)[J].Age (Dordr), 2006,28(3):283-296.
[8]Cheng XR,Yang Y,Zhou WX,et al.Expression of VGLUTs contributes to degeneration and acquisition of learning and memory[J].Neurobiol Learn Mem,2011,95(3):361-375.
[9]Spangler EL,Patel N,Speer D,et al.Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM):age and strain comparisons of SAM P8 and R1 [J].J Gerontol A Biol Sci Med Sci,2002,57(2):B61-68.
[10]Strong R.Reddy V,Morley JE.Cholinergic deficits in the septal-hippocampal pathway of the SAM-P/8 senescence accelerated mouse[J].Brain Res,2003, 966(1):150-156.
[11]Morley JE,Kumar VB,Bernardo AE,et al.p-Amyloid precursor polypeptide in SAMP8 mice affects learning and memory[J].Peptides,2000,21 (12):1761-1767.
[12]Kumar VB,Farr SA,Flood JF,et al.Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice[J].Peptides,2000,21(12):1769-1775.
[13]Pelegri C,Canudas AM,del Valle J,et al.Increased permeability of blood-brain barrier on the hippocampus of a murine model of senescence[J].Mech Ageing Dev,2007,128(9):522-528.
[14]Zhu Y,Lee CC,Lam WP,et al.Cell death in the Purkinje cells of the cerebellum of senescence accelerated mouse (SAMP(8))[J].Biogerontology,2007,8(5):537-544.
[15]施晓芸,陈晓春,石艳清,等.快速老化小鼠P8肾脏衰老的病理特点[J].中国老年学杂志,2010,3：43-45.
[16]Liu Y,He J,Ji S,et al.Comparative studies of early liver dysfunction in senescence-accelerated mouse using mitochondrial proteomics approaches[J].Mol Cell Proteomics,2008,7(9):1737-1747.
[17]Rebrin I,Zicoker S,Wedekind KJ,et al.Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse[J].Free Radic Biol Med,2005,39(4):549-557.
[18]Gutierrez-Cuesta J,Sureda FX,Romeu M.et al.Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8[J].J Pineal Res,2007,42(4):394-402.
[19]Chen CC,Liu MH,Wang MF,et al.Effects of aging and dietary antler supplementation on the calcium-regulating hormones and bone status in ovariectomized SAMP8 mice[J].Chin J Physiol,2007,50(6):308-314.
[20]Yang S,Qiao H,Wen L,et al.D-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8[J].Neurosci Lett,2005,379(1):7-12.
[21]唐勇,郭玲玲,张琪,等.快速老化小鼠肾脏组织-1H-NMR谱图变化及电针对其的影响[J].成都中医药大学学报,2009,2：3-6.
[22]蒋宁,周文霞,张永祥.应用代谢组学方法研究比较六味及八味地黄汤的作用机理[J].中药药理与临床,2007,5：45.
[23]朱宏,董克礼,李广成.“补肾活血”针刺法对SAMP8小鼠海马蛋白质表达的影响[J].中国老年学杂志,2011,31(23)：4613-4616.
[24]Wang Q,Matsumoto Y,Shindo T,et al.Neural stem cells transplantation in cortex in a mouse model of Alzheimer's disease[J].J Med Invest,2006, 53(1-2):61-69.
[25]Wang D,Noda Y,Zhou Y,et al.The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice:involvement of dopaminergic systems[J].Neuropsychopharmacology,2007,32(6):1261-1271.
[26]Prediger RD,Franco JL,Pandolfo P,et al.Differential susceptibility following β-amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice: Evidence for a dissociation between cognitive deficits and the glutathione system response[J].Behav Brain Res,2007,177:205-213.
[27]Bagheri M,Joghataei MT,Mohseni S,et al.Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's disease[J]. Neurobiol Learn Mem,2011,95(3):270-276.
[28]Alessandro Biffi,Steven M.Greenberg.Cerebral amyloid angiopathy:A systematic review[J].J Clin Neurol 2011;7:1-9.
[29]Gouras GK,Tampellini D,Takahashi RH,et al.Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease[J].Acta Neuropathol, 2010,119(5):523-541.
[30]Hernandez F,de Barreda EG,Fuster-Matanzo A,et al.The role of GSK3 in Alzheimer disease[J].Brain Res Bull,2009,80(4-5):248-250.
[31]Malm T,Ort M,Tahtivaara L,et al.beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits[J].Proc Natl Acad Sci U S A,2006,103(23):8852-8857.
[32]Lee JW,Lee YK,Yuk DY,et al.Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation[J].J Neuroinflammation,2008,5:37.
[33]原淑娟,张志雄,吴定宗,等.D-半乳糖对大鼠空间学习记忆行为与脑海马结构电生理以及突触形态学的影响[J].中国临床康复,2005,37：184-187.
[34]Medeiros R,Prediger RD,Passos GF,et al.Connecting TNF-α signaling pathways to iNOS expression in a mouse model of Alzheimer's disease:relevance for the behavioral and synaptic deficits induced by amyloid β protein[J].J Neurosci,2007,27(20):5394-5404.
[35]Watanabe T,Iwasaki K,Ishikane S,et al.Spatial memory impairment without apoptosis induced by the combination of Beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats[J].J Pharmacol Sci,2008,106:84-91.
[36]Bales KR,Liu F,Wu S,et al.Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice[J].J Neurosci,2009, 29(21):6771-6779.
[37]Ray S,Howells C,Eaton ED,et al.Tg2576 cortical neurons that express human Ab are susceptible to extracellular Aβ-induced,K+efflux dependent neurodegeneration[J].PLoS One,2011,6(4):e 19026.
[38]Middei S,Roberto A,Berretta N,et al.Learning discloses abnormal structural and functional plasticity at hippocampal synapses in the APP23 mouse model of Alzheimer's disease[J].Learn Mem,2010,17(5):236-240.
[39]Yang DS,Stavrides P,Mohan PS,et al.Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits[J].Brain,2011,134(Pt 1):258-277.
[40]Duyckaerts C,Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences[J].Acta Neuropathol,2008, 115(1):5-38.
[41]Bien-Ly N,Andrews-Zwilling Y,Xu Q,et al.C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice.[J].Proc Natl Acad Sci U S A,2011,108(10):4236-4241.
[42]Clinton LK,Billings LM,Green KN,et al.Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice[J].Neurobiol Dis,2007, 28(1):76-82.
[1]Christian Humpel.Chronic mild cerebrovascular dysfunction as a cause for Alzheimer's disease[J]? Exp Gerontol,2011,46(4):225-232.
[2]Alzheimer's Association,Thies W,Bleiler L.2011 Alzheimer's disease facts and figures[J].Alzheimers Dement,2011,7(2):208-244.
[3]Berislav V.Zlokovic.Neurovascular mechanisms of Alzheimer's neurodegeneration[J].Neuro sciences.2005, April,28(4):202-208.
[1]R.D.S.Prediger,R.Medeiros,P.Pandolfo,et al.Genetic deletion or antagonism of Kinin Bl and B2 receptors improves cognitive deficits in a mouse model of Alzheimer's disease[J].Neuroscience,2008,151:631-643.
[2]George Paxinos Keith B.J.Franklin.The mouse brain[M].Academic Press,2001,50.
[3]Alberto E.Musto,Mark S.Samii,Justin F.Hayes.Different phases of afterdischarge during rapid kindling procedure in mice[J].Epilepsy Res,2009,85(2-3):199-205.
[4]Jerry J Buccafusco.Methods of Behavior Analysis in Neuroscience[M].Boca Raton (FL):CRC Press,2009,6.
[5]Rodrigo Medeiros,Rui D.S.Prediger,Giselle F.Passos.et al.Connecting TNF-α signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid (3 protein[J].The Journal of Neuroscience,2007,27(20):5394-5404.
[6]Tomobe K,Nomura Y.Neurochemistry,neuropathology,and heredity in SAMP8: a mouse model of senescence[J].Neurochem Res,2009,34(4):660-669.
[7]Tajes M,Gutierrez-Cuesta J,Folch J,et al.Neuroprotective role of intermittent fasting in senescence-accelerated mice P8 (SAMP8) [J].Exp Gerontol, 2010,45(9):702-710.
[1]Parihar MS,Brewer GJ.Amyloid Beta as a Modulator of Synaptic Plasticity[J].J Alzheimers Dis,2010,22(3):741-763.
[2]Seeman P,Seeman N.Alzheimer's Disease:β-Amyloid Plaque Formation in Human Brain[J].Synapse,2011,65(12):1289-1297.
[3]Manich G,Mercader C,del Valle J,et al.Characterization of amyloid-β granules in the hippocampus of SAMP8 mice[J].J Alzheimers Dis,2011,25(3):535-546.
[4]Zheng H,Koo EH.The amyloid precursor protein:beyond amyloid[J].Mol Neurodegener,2006,1:5.
[5]O'Brien RJ.Wong PC.Amyloid Precursor Protein Processing and Alzheimer's Disease[J].Annu Rev Neurosci,2011,34:185-204.
[6]Bateman RJ,Klunk WE.Measuring target effect of proposed disease-modifying therapies in Alzheimer's disease[J].Neurotherapeutics,2008,5(3):381-390.
[7]Kumar VB,Franko M,Banks WA,et al.Increase in presenilin 1 (PS1) levels in senescence-accelerated mice (SAMP8) may indirectly impair memory by affecting amyloid precursor protein (APP) processing[J].J Exp Biol,2009,212(Pt 4):494-498.
[8]Niikura T,Sidahmed E,Hirata-Fukae C,et al.A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice[J].PLoS One,2011,6(1):e 16259.
[9]Laibaik Parka,Gang Wanga,Ping Zhou,et al.Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β[J].Proc Natl Acad Sci U S A,2011,108(12):5063-5068.
[10]Magdalena Sastre,Jochen Walter,Steve M Gentleman,et al.Interactions between APP secretases and inflammatory mediators[J].J Neuroinflammation. 2008,18(5):25-35.
[11]Koji Tomobe,Yasuyuki Nomura.Neurochemistry,neuropathology,and heredity in SAMP8:a mouse model of senescence[J].Neurochem Res,2009,34:660-669.
[12]Ahmed RR,Holler CJ,Webb RL,et al.BACE1 and BACE2 enzymatic activities in Alzheimer's disease[J].J Neurochem,2010,112(4):1045-1053.
[13]Colciaghi F,Marcello E,Borroni B,et al.Platelet APP,ADAM 10 and BACE alterations in the early stages of Alzheimer disease[J]. Neurology,2004. 62(3):498-501.
[14]Venugopal C,Demos CM,Rao KS,et al.Beta-secretase:structure,function,and evolution[J].CNS Neurol Disord Drug Targets,2008,7(3):278-294.
[15]Sato N,Ueki A,Ueno H,et al.IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type[J].Curr Gerontol Geriatr Res,2008:858759.
[16]Dorfman VB,Pasquini L,Riudavets M,et al.Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease[J].Neurobiol Aging,2010,31(10):1743-1757.
[17]de Tullio MB,Morelli L,Castano EM.The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme:a biological perspective[J]. Prion.2008 Apr-Jun;2(2):51-6.
[18]Kim MS,Goo JS,Kim JE,et al.Overexpression of Insulin Degrading Enzyme could Greatly Contribute to Insulin Down-regulation Induced by Short-Term Swimming Exercise[J].Lab Anim Res,2011,27(1):29-36.
[19]Neant-Fery M,Garcia-Ordonez RD,Logan TP,et al.Molecular basis for the thiol sensitivity of insulin-degrading enzyme.[J].Proc Natl Acad Sci U S A,2008,105(28):9582-9587.
[20]Vepslinen S,Hiltunen M,Helisalmi S,et al.Increased expression of Abeta degrading enzyme IDE in the cortex of transgenic mice with Alzheimer's disease-like neuropathology[J].Neurosci Lett,2008,438(2):216-220.
[21]May P,Rohlmann A,Bock HH,et al.Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice[J].Mol Cell Biol,2004,24(20):8872-8883.
[22]Meijer AB,Rohlena J,van der Zwaan C,et al.Functional duplication of ligand-binding domains within low-density lipoprotein receptor-related protein for interaction with receptor associated protein,alpha2-macroglobulin,factor IXa and factor VIII[J].Biochim Biophys Acta,2007,1774(6):714-722.
[23]Deane R,Wu Z,Sagare A,et al.LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms[J].Neuron,2004,43(3):333-344.
[24]Robert D.Bell,Abhay Sagare.Alan E.Friedman,et al.Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system[J].J Cereb Blood Flow Metab,2007, 27(5):909-918.
[25]Rashid Deane,Zhenhua Wu.Berislav V.Zlokovic.RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier[J].Stroke,2004,35:2628-2631.
[26]Donahue JE,Flaherty SL,Johanson CE,et al.RAGE,LRP-1,and amyloid-beta protein in Alzheimer's disease[J].Acta Neuropathol,2006,112:405-415.
[27]Han SH,Kim YH,Inhee MJ.RAGE:The Beneficial and Deleterious Effects by Diverse Mechanisms of Actions[J].Mol Cells,2011,31:91-97.
[28]Kandimalla KK,Curran GL,Holasek SS,et al.Pharmacokinetic analysis of the blood-brain barrier transport of 1251-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation[J].J Pharmacol Exp Ther,2005,313(3):1370-1378.
[29]Qiang Liu,Celina V.Zerbinattil,Juan Zhang,et al.Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1 [J].Neuron,2007,56(1):66-78.
[30]Mielke MM,Leoutsakos JM,Tschanz JT,et al.Interaction between vascular factors and the APOE ε4 allele in predicting rate of progression in Alzheimer's disease[J].J Alzheimers Dis,2011,26(1):127-134.
[31]Tai LM,Youmans KL,Jungbauer L,et al.Introducing Human APOE into A[3 Transgenic Mouse Models[J].Int J Alzheimers Dis,2011,2011:810981.
[32]Anna P.Lillis,Lauren B.Van Duyn,Joanne E.Murphy-Ullrich,et al.The low density lipoprotein receptor-related protein 1:Unique tissue-specific functions revealed by selective gene knockout studies[J].Physiol Rev,2008,88(3):887-918.
[33]Yoshiike Y,Minai R,Matsuo Y,et al.Amyloid oligomer conformation in a group of natively folded proteins[J].PLoS One,2008,3(9):e3235.
[34]Edwards TL,Pericak-Vance M,Gilbert JR,et al.An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE,A2M,and LRRTM3[J].Am J Med Genet B Neuropsychiatr Genet.2009 Jul 5;150B(5):721-35.
[2]K.Maurer.Historical background of Alzheimer's research done 100 years ago[J].J Neural Transm,2006,113:1597-1601.
[3]Nelson PT,Head E,Schmitt FA,et al.Alzheimer's disease is not "brain aging" neuropathological,genetic,and epidemiological human studies[J].Acta Neuropathol,2011,121(5):571-587.
[4]Grand JH,Caspar S,Macdonald SW.Clinical features and multidisciplinary approaches to dementia care[J].J Multidiscip Healthc,2011,4:125-147.
[5]Hellstrom-Lindahl E,Viitanen M,Marutle A.Comparison of Abeta levels in the brain of familial and sporadic Alzheimer's disease[J].Neurochem Int, 2009,55(4):243-252.
[6]Janicki SC,Schupf N.Hormonal influences on cognition and risk for Alzheimer's disease[J].Curr Neurol Neurosci Rep,2010,10(5):359-366.
[7]Mehta KM,Stewart AL,Langa KM,et al."Below average" self-assessed school performance and Alzheimer's disease in the Aging,Demographics,and Memory Study[J].Alzheimers Dement,2009,5(5):380-387.
[8]Beeri MS,Goldbourt U.Late-life dementia predicts mortality beyond established midlife risk factors[J].Am J Geriatr Psychiatry,2011,19(1):79-87.
[9]Santibanez M,Bolumar F,Garcia AM.Occupational risk factors in Alzheimer's disease:a review assessing the quality of published epidemiological studies[J].Occup Environ Med,2007,64(11):723-732.
[10]Chen JH,Lin KP,Chen YC.Risk Factors for Dementia[J].J Formos Med Assoc, 2009,108(10):754-764.
[11]Neafsey EJ,Collins MA.Moderate alcohol consumption and cognitive risk[J].Neuropsychiatr Dis Treat,2011,7:465-484.
[12]Ciobica A,Padurariu M.Bild W,et al.Cardiovascular risk factors as potential markers for mild cognitive impairment and Alzheimer's disease[J].Psychiatr Danub,2011,23(4):340-346.
[13]Reitz C.Tang MX,Schupf N,et al.Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease[J].Arch Neurol,2010,67(12):1491-1497.
[14]Schrijvers EM,Witteman JC,Sijbrands EJ,et al.Insulin metabolism and the risk of Alzheimer disease:the Rotterdam Study[J].Neurology,2010, 75(22):1982-1987.
[15]Doherty GH.Obesity and the ageing brain:could leptin play a role in neurodegeneration[J]? Curr Gerontol Geriatr Res,2011,2011:708154.
[16]Flirski M,Sobow T,Kloszewska I.Behavioural genetics of Alzheimer's disease: a comprehensive review[J].Arch Med Sci,2011,7(2):195-210.
[17]Lopez OL.The growing burden of Alzheimer's disease[J].Am J Manag Care, 2011,13:S339-345.
[18]R.A.Armstrong.The Pathogenesis of Alzheimer's Disease:A Reevaluation of the Amyloid Cascade Hypothesis[J].Int J Alzheimers Dis,2011,Feb 7:1-6.
[19]Michael S Wolfe,Suzanne Y Guenette.APP at a glance[J].J Cell Sci,2007,120(18):3157-3161.
[20]O'Brien RJ,Wong PC.Amyloid Precursor Protein Processing and Alzheimer's Disease[J].Annu Rev Neurosci,2011,34:185-204.
[21]Hui Zheng,Edward H Koo.Biology and pathophysiology of the amyloid precursor protein[J].Mol.Neurodegener,2011,6(1):27-42.
[22]Thinakaran G,Koo EH.Amyloid precursor protein trafficking,processing,and function[J].J Biol Chem,2008,283(44):29615-29619.
[23]Alessandro Biffi,Steven M.Greenberg.Cerebral amyloid angiopathy:A systematic review[J].J Clin Neurol 2011;7:1-9.
[24]Gouras GK,Tampellini D,Takahashi RH,et al.Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease[J].Acta Neuropathol, 2010,119(5):523-541.
[25]Pleckaityte M.Alzheimer's disease:a molecular mechanism,new hypotheses,and therapeutic strategies[J].Medicina (Kaunas),2010,46(1):70-76.
[26]Hernandez F,de Barreda EG,Fuster-Matanzo A,et al.The role of GSK3 in Alzheimer disease[J].Brain Res Bull,2009,80(4-5):248-250.
[27]Parihar MS,Brewer GJ.Amyloid Beta as a Modulator of Synaptic Plasticity[J].J Alzheimers Dis,2010,22(3):741-763.
[28]Struble RG,Ala T.Patrylo PR,et al.Is brain amyloid production a cause or a result of dementia of the Alzheimer's type[J]? J Alzheimers Dis, 2010,22(2):393-399.
[29]Gregory A.Elder,Miguel A.Gama Sosa,Rita De Gasperi.Transgenic Mouse Models of Alzheimer's Disease[J].Mt Sinai J Med,2010,77(1):69-81.
[30]Shuko Takeda,Naoyuki Sato,Kazue Niisato,et al.Validation of Aβ1-40 administration into mouse cerebroventricles as an animal model for Alzheimer disease[J].Brain research.2009,1280:137-147.
[31]Perluigi M,Butterfield DA.Oxidative Stress and Down Syndrome:A Route toward Alzheimer-Like Dementia[J].Curr Gerontol Geriatr Res, 2012,2012:724904.
[32]De Meyer G,Shapiro F,Vanderstichele H,et al.Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people[J].Arch Neurol,2010,67(8):949-956.
[33]Kaddurah-Daouk R,Rozen S,Matson W,et al.Metabolomic changes in autopsy-confirmed Alzheimer's disease[J].Alzheimers Dement,2011, 7(3):309-317.
[34]Mary Griffin Krone,Andrij Baumketner,Summer L.Bernstein,et al.Effects of familial mutations on the folding nucleation of the Alzheimer Amyloid β-protein[J].J Mol Biol,2008,381(1):221-228.
[35]Nation DA,Hong S,Jak AJ.Stress,exercise,and Alzheimer's disease:A neurovascular pathway[J].Med Hypotheses,2011,76(6):847-854.
[36]Berislav V.Zlokovic.Neurovascular mechanisms of Alzheimer's neurodegeneration[J].Neurosciences.2005,April,28(4):202-208.
[37]Zlokovic BV.The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders[J].Neuron,2008,57(2):178-201.
[38]Smith EE,Greenberg SM.Beta-amyloid,blood vessels,and brain function[J]. Stroke,2009,40(7):2601-2606.
[39]Grammas P.Neurovascular dysfunction,inflammation and endothelial activation:Implications for the pathogenesis of Alzheimer's disease[J].J Neuroinflammation,2011,8:26.
[40]Matsunari I,Samuraki M,Chen WP,et al.Comparison of 18F-FDG PET and optimized voxel-based morphometry for detection of Alzheimer's disease:aging effect on diagnostic performance[J].J Nucl Med,2007,48(12):1961-1970.
[41]Kumar-Singh S.Cerebral amyloid angiopathy:pathogenetic mechanisms and link to dense amyloid plaques[J].Genes Brain Behav,2008,1:67-82.
[42]Grinberg LT,Thal DR.Vascular pathology in the aged human brain[J].Acta Neuropathol,2010,119:277-290.
[43]Rashid Deane,Zhenhua Wu,Berislav V.Zlokovic.RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier[J].Stroke.2004,35:2628-2631.
[44]Sagare A,Deane R,Bell RD,et al.Clearance of amyloid-beta by circulating lipoprotein receptors[J].Nat Med.2007,13(9):1029-1031.
[45]R.E.Tanzi,R.D.Moir,S.L.Wagner.Clearance of Alzheimer's Aβ peptide:the many roads to perdition[J].Neuron,2004,43:605-608.
[46]Shibata M,Yamada S,Kumar SR,et al.Clearance of Alzheimer's amyloid-β(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier[J].J Clin Invest,2000,106(12):1489-1499.
[47]R Deane,RD Bell,A Sagare,et al.Clearance of amyloid-β peptide across the blood-brain barrier:implication for therapies in Alzheimer's disease[J].CNS Neurol Disord Drug Targets,2009,8(1):16-30.
[48]R.Deane,A.Sagare,B.Zlokovic.The Role of the Cell Surface LRP and Soluble LRP in Blood-Brain Barrier Ap Clearance in Alzheimer's Disease[J].Curr Pharm Des,2008,14(16):1601-1605.
[49]Milan Fiala,Robert Veerhuis.Biomarkers of inflammation and amyloid-β phagocytosis in patients at risk of Alzheimer disease[J].Exp Gerontol,2010,45(1): 57-63.
[50]Pantoni L,Gorelick P.Advances in Vascular Cognitive Impairment 2010[J].Stroke,2011,42:291-293.
[51]Kalaria RN,Maestre GE,Arizaga R,et al.Alzheimer's disease and vascular dementia in developing countries:prevalence,management,and risk factors[J].Lancet Neurol,2008,7(9):812-826.
[52]Robert D.Bell1,Berislav V.Zlokovic.Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease[J].Acta Neuropathol. 2009,118(1):103-113.
[53]Franceschi C,Valensin S.Bonafe M,et al.The network and the remodeling theories of aging:historical background and new perspectives[J].Exp Gerontol,2000,35(6-7):879-896.
[54]Hickman SE,Allison EK,Khoury JE.Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice[J].J Neurosci,2008,28(33):8354-8360.
[55]JJ Rodriguez,J Witton,M Olabarria,et al.Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease[J].Cell Death Dis,2010,1:1-6.
[56]Saez TE,Pehar M,Vargas M,et al.Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons[J].In Vivo,2004,18(3):275-280.
[57]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis[J].Science,1992,256(5054):184-185.
[58]Butterfield DA,Reed T,Newman SF.et al.Roles of Amyloid β-Peptide-Associated Oxidative Stress and Brain Protein Modifications in the Pathogenesis of Alzheimer's Disease and Mild Cognitive Impairment[J].Free Radic Biol Med,2007,43(5):658-677.
[59]Axelsen PH,Komatsu H,Murray Ⅳ.Oxidative Stress and Cell Membranes in the Pathogenesis of Alzheimer's Disease[J].Physiology (Bethesda), 2011,26(1):54-69.
[60]Atri A.Effective pharmacological management of Alzheimer's disease[J].Am J Manag Care,2011,13:S346-355.
[61]Rodrigo O.Kuljis.Integrative understanding of emergent brain properties,quantum brain hypotheses,and connectome alterations in dementia are key challenges to conquer Alzheimer's disease[J].Front Neurol,2010,26:1-15.
[62]Wang S,Wang R,Chen L,et al.Expression and functional profiling of neprilysin,insulin degrading enzyme and endothelin converting enzyme in prospectively studied elderly and Alzheimer's brain[J].J Neurochem,2010,115(1): 47-57.
[63]Numata K,Kaplan DL.Mechanisms of Enzymatic Degradation of Amyloid Beta Microfibrils Generating Nanofilaments and Nanospheres Related to Cytotoxicity[J].Biochemistry,2010,49(15):3254-3260.
[64]Luchsinger JA,Gustafson DR.Adiposity,type 2 diabetes,and Alzheimer's disease[J].J Alzheimers Dis,2009,16(4):693-704.
[65]Cheng D,Noble J,Tang MX,et al.Type 2 diabetes and late-onset Alzheimer's disease[J].Dement Geriatr Cogn Disord,2011,31 (6):424-430.
[66]Bezprozvanny I,Mattson MP.Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease[J].Trends Neurosci,2008,31 (9):454-463.
[67]Kawahara M,Kato-Negishi M.Link between Aluminum and the Pathogenesis of Alzheimer's Disease:The Integration of the Aluminum and Amyloid Cascade Hypotheses[J].Int J Alzheimers Dis,2011,2011:276393.
[68]Strozyk D,Launer LJ,Adlard PA,et al.Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid[J].Neurobiol Aging, 2009,30(7):1069-1077.
[69]Beel AJ,Sakakura M,Barrett PJ,et al.Direct Binding of Cholesterol to the Amyloid Precursor Protein:An Important Interaction in Lipid-Alzheimer's Disease Relationships[J]? Biochim Biophys Acta,2010,1801(8):975-982.
[70]Russell H.Swerdlow,Jeffrey M.Burns,Shaharyar M.Khan.The Alzheimer's Disease Mitochondrial Cascade Hypothesis[J].J Alzheimers Dis,2010,20(Suppl 2):265-279.
[71]Escames G,Lopez A,Garcia JA,et al.The Role of Mitochondria in Brain Aging and the Effects of Melatonin[J].Curr Neuropharmacol,2010,8(3):182-193.
[72]Selkoe DJ.Alzheimer's disease is a synaptic failure[J]. Science,2002, 298(5594):789-791.
[73]Ondrejcak T,Klyubin I,Hu NW,et al.Alzheimer's disease amyloid beta-protein and synaptic function[J].Neuromolecular Med,2010,12(1):13-26.
[74]Bekris LM,Yu CE,Bird TD,et al.Genetics of Alzheimer Disease[J].J Geriatr Psychiatry Neurol,2010,23(4):213-227.
[75]Ertekin-Taner N.Genetics of Alzheimer's Disease:A Centennial Review[J].Neurol Clin,2007,25(3):611-v.
[76]DeMichele-Sweet MA,Sweet RA.Genetics of Psychosis in Alzheimer Disease: A Review[J].J Alzheimers Dis,2010,19(3):761-780.
[77]Pimplikar SW,Nixon RA,Robakis NK,et al.Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis[J].J Neurosci, 2010,30(45):14946-14954.
[78]Mayeux R,Reitz C,Brickman AM.et al.Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment—Part 1[J]. Alzheimers Dement.2011,7(1):15-34.
[79]Seshadri S,Beiser A,Au R,et al.Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment—Part 2[J]. Alzheimers Dement,2011,7(1):35-52.
[80]Jicha GA,Abner EL,Schmitt FA,et al.Preclinical AD Workgroup staging: pathological correlates and potential challenges[J].Neurobiol Aging,2012, 33(3):622.el-622.e16.
[81]Cumming JL.Biomarkers in Alzheimer's disease drug development[J]. Alzheimers Dement,2011,7(3):e13-44.
[82]Sperling RA,Aisen PS,Beckett LA,et al.Toward defining the preclinical stages of Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):280-292.
[83]Forlenza OV,Diniz BS,Gattaz WF.Diagnosis and biomarkers of predementia in Alzheimer's disease[J].BMC Med,2010,8:89.
[84]Albert MS,DeKosky ST,Dickson D,et al.The diagnosis of mild cognitive impairment due to Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):270-279.
[85]Jack CR Jr,Barkhof F,Bernstein MA,et al.Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease[J].Alzheimers Dement, 2011,7(4):474-485.e4.
[86]Riverol M,Lopez OL.Biomarkers in Alzheimer's disease[J].Front Neurol, 2011,2:46.
[87]Alzheimer's Association,Thies W,Bleiler L.2011 Alzheimer's disease facts and figures[J].Alzheimers Dement,2011,7(2):208-244.
[88]Seyfried LS,Kales HC,Ignacio RV,et al.Predictors of suicide in patients with dementia[J].Alzheimers Dement,2011,7(6):567-573.
[89]Jack CR Jr,Albert MS,Knopman DS,et al.Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011,7(3):257-262.
[90]McKhann GM,Knopman DS,Chertkow H,et al.The diagnosis of dementia due to Alzheimer's disease:Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J].Alzheimers Dement,2011 May;7(3):263-269.
[91]Demarin V,Zavoreo I,Kes VB,et al.Biomarkers in Alzheimer's disease[J].Clin Chem Lab Med,2011,49(5):773-778.
[92]Griffiths HH,Morten IJ,Hooper NM.Emerging and potential therapies for Alzheimer's disease[J].Expert Opin Ther Targets,2008,12(6):693-704.
[93]Sarah L Cole,Robert Vassar.The Alzheimer's disease beta-secretase enzyme,BACE1 [J].Molecular Neurodegeneration 2007,2:22.
[94]Huilin Li,Michael S.Wolfe,Dennis J.Selkoe.Toward structural elucidation of the y-secretase complex[J].Structure,2009,17(3):326-334.
[95]Tomita T,Wong PC.Selectivity to amyloid-β precursor protein cleavage provides hope against Alzheimer's[J].Alzheimers Res Ther,2011,3(2):7.
[96]Sastre M,Walter J,Gentleman SM.Interactions between APP secretases and inflammatory mediators[J].J Neuroinflammation,2008,5:25.
[97]Weinmann S,Roll S,Schwarzbach C,et al.Effects of Ginkgo biloba in dementia:systematic review and meta-analysis[J].B M C Geriatr,2010,10:14.
[98]Daniel Hafez,Jeffrey Y.Huang,Alexis M.Huynh,et al.Neprilysin-2 Is an Important β-Amyloid Degrading Enzyme[J].Am J Pathol,2011,178(1):306-312.
[99]Carrasquillo MM,Belbin O,Zou F.et al.Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA,Aβ,and Alzheimer's Disease[J].PLoS ONE,2010,5(1):e8764.
[100]Amijee H,Scopes DI.The Quest for Small Molecules as Amyloid Inhibiting Therapies for Alzheimer's Disease[J].J Alzheimers Dis,2009,17(1):33-47.
[101]Creed MC,Milgram NW.Amyloid-modifying therapies for Alzheimer's disease:therapeutic progress and its implications[J].Age (Dordr),2010,32(3):365-384.
[102]Salloway S,Sperling R,Keren R,et al.A phase 2 randomized trial of ELND005,scyllo-inositol,in mild to moderate Alzheimer disease[J]. Neurology, 2011,77(13):1253-1262.
[103]Fu HJ,Liu B,Frost JL,et al.Amyloid-β Immunotherapy for Alzheimer's Disease[J].CNS Neurol Disord Drug Targets,2010,9(2):197-206.
[104]Town T.Alternative Aβ Immunotherapy Approaches for Alzheimer's Disease[J].CNS Neurol Disord Drug Targets,2009,8(2):114-127.
[105]McClendon MJ,Hernandez S,Smyth KA,et al.Memantine and acetylcholinesterase inhibitor treatment in cases of CDR 0.5 or questionable impairment[J].J Alzheimers Dis.2009,16(3):577-583.
[106]Hansen RA,Gartlehner G,Webb AP,et al.Efficacy and safety of donepezil,galantamine,and rivastigmine for the treatment of Alzheimer's disease:a systematic review and meta-analysis[J].Clin Interv Aging,2008,3(2):211-225.
[107]Lockhart IA,Orme ME,Mitchell SA.The Efficacy of Licensed-Indication Use of Donepezil and Memantine Monotherapies for Treating Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer's Disease: Systematic Review and Meta-Analysis[J].Dement Geriatr Cogn Dis Extra, 2011,1(1):212-227.
[108]Pohanka M.Cholinesterases,a target of pharmacology and toxicology[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2011,155(3):219-229.
[109]Thomas SJ,Grossberg GT.Memantine:a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias[J].Clin Interv Aging,2009,4:367-377.
[110]Anekonda TS,Quinn JF,Harris C,et al.L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease[J].Neurobiol Dis,2011,41(1):62-70.
[111]Srinivasan V,Spence DW,Pandi-Perumal SR,et al.Melatonin in mitochondrial dysfunction and related disorders[J].Int J Alzheimers Dis, 2011,2011:326320.
[112]Iqbal K,Liu F,Gong CX,et al.Tau in Alzheimer disease and related tauopathies[J].Curr Alzheimer Res,2010,7(8):656-664.
[113]Bush AI,Tanzi RE.Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis[J].Neurotherapeutics,2008,5(3):421-432.
[114]Zotova E,Nicoll JA,Kalaria R,et al.Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy[J].Alzheimers Res Ther,2010,2(1):1.
[115]Davies P,Koppel J.Mechanism-based treatments for Alzheimer's disease[J].Dialogues Clin Neurosci,2009,11 (2):159-169.
[116]Thoonsen H,Richard E,Bentham P,et al.Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage:cause for concern[J]? Stroke, 2010,41 (11):2690-2692.
[117]Sergio A.Rosales-Corral,Dario Acuna-Castroviejo,Ana CotoMontes,et al.Alzheimer's disease:pathological mechanisms and the beneficial role of melatonin[J].J.Pineal Res,2011,52(2):167-202.
[118]Stone JG,Casadesus G,Gustaw-Rothenberg K,et al.Frontiers in Alzheimer's Disease Therapeutics[J].Ther Adv Chronic Dis,2011,2(1):9-23.
[119]Ryan J,Scali J,Carriere I,et al.Hormonal treatment,mild cognitive impairment and Alzheimer's Disease[J].Int Psychogeriatr,2008,20(1):47-56.
[1]沈自尹,黄建华,林伟,等.从整体论到系统生物学进行肾虚和衰老的研究[J].中国中西医结合杂志,2009,6(6)：548-550.
[2]刘宁,郭蕾.阿尔茨海默病中医认识[J].中华中医药学刊,2011,29(6)：1254-1255.
[3]卿照前.六味地黄丸延缓老年痴呆症50例疗效观察[J].中国中医药科技,2007,5：75-76.
[4]王迪,尚晓玲.六味地黄丸防治老年病[J].中国老年学杂志,2011,3：161-164.
[5]张伟伟,刘银辉,孙启新.六味地黄丸对老年大鼠神经系统的抗衰老作用[J].陕西中医,2010,31(9)：1264-1265.
[6]易健,刘柏炎,蔡光先.超微六味地黄汤对老年痴呆大鼠认知功能和脑组织碱性成纤维生长因子表达的影响[J].中国实验方剂学杂志,2011,21：149-152.
[7]Zhang WW,Sun QX,Liu YH,et al.Chronic administration of Liu Wei Dihuang protects rat's brain against D-galactose-induced impairment of cholinergic system[J].Sheng Li Xue Bao,2011,63(3):245-255.
[8]Lee KS,Lim BV,Chang HK,et al.Liuweidihuang-tang improves spatial memory function and increases neurogenesis in the dentate gyrus in rats[J].Fitoterapia, 2005,76(6):514-519.
[9]Wu CR,Lin LW,Wang WH,et al. The ameliorating effects of LiuWei Dihuang Wang on cycloheximide-induced impairment of passive avoidance performance in rats[J]. J Ethnopharmacol,2007,113(1):79-84.
[10]冯炯,臧敏.六味地黄丸对痴呆模型小鼠学习记忆及细胞因子的影响[J].山东中医杂志,2010,4：50-51.
[11]刘继平,兰洲,傅强,等.六味地黄醇提水洗脱部位对D-半乳糖所致小鼠衰老模型的影响[J].药学与临床研究,2011,3：40-43.
[12]富宏,王学美,刘庚信,等.加味五子衍宗颗粒对轻度认知功能障碍患者记忆功能及血清β淀粉样蛋白的影响[J].中国老年学杂志,2007,8：15-17.
[13]黎巍威,王学美.中医从“肾”防治阿尔茨海默病的现代研究[J].中国实验方剂学杂志,2010,16(13)：227-230.
[14]褚松龄,王学美,富宏,等.加味五子衍宗方及有效组分对记忆障碍小鼠中枢胆碱能系统的影响[J].中国中医药信息杂志,2006,2：21-22.
[15]王建明.七福饮加味治疗老年性痴呆32例[J].辽宁中医杂志,2002,1：45.
[16]兴桂华,林春荣,张晓杰,等.七福饮对Aβ1-42诱导老年性痴呆模型大鼠海马 神经细胞凋亡的保护作用[J].中国实验方剂学杂志,2010,12：146-149.
[17]王玉宇.左归饮加减治疗老年性痴呆60例[J].海南医学,2001,2：40-41.
[18]王燕.左归饮对衰老模型小鼠血清SOD GSH-Px MDA及IL-2的影响[J].中华中医药学刊,2009,7：160-161.
[19]李枝朝.地黄饮子治疗老年痴呆症18例[J].四川中医,2011,2：93.
[20]李凌云.地黄饮子在老年脑病中的临床应用[J].中国民间疗法,2010,6：35.
[21]牛英才,董妙先,兴桂华,等.Ap损伤后大鼠SOD和MDA的变化及补肾活血化痰法的干预作用[J].中华中医药学刊,2008,(1)：75-77.
[22]谢宁,牛英才,宋琳,等.加减地黄饮子对Aβ-40所致痴呆大鼠学习记忆、脑酶活性的影响[J].中医药信息,2004,2：60-61.
[23]陈岩,袁勇.活脑方治疗阿尔茨海默病肾虚髓减证临床研究[J].山东医药,2008,32：87-88.
[24]王树炜,金秀梅.益智醒脑汤治疗老年性痴呆50例[J].四川中医,2005,5：51.
[25]夏宗勤,胡雅儿,张永芳,等.一些重要滋肾阴中药防治神经退行性病变的分子机理[C].中国核科学技术进展报告——中国核学会2009年学术年会论文集,2009,11：36-41.
[26]徐进友.从风痰瘀论治老年性痴呆[J].辽宁中医药大学学报.2012,2：168-169.
[27]贾怡蓓,白雪,张宇红,等.从瘀辨治不同法则治疗Alzheimer病疗效的临床观察[J].中西医结合心脑血管病杂志,2010,8(1)：37-39.
[28]武宏.通窍活血汤加减治疗血管性痴呆40例[J].陕西中医,2006,11：29-30.
[29]Liu CZ,Zhou LH,Shui Z,et al.Clinical Observation Tongqiao Huoxue Tang and Buyang Huanwu Tang for Treatment of Vascular Dementia—A report of 36 Cases[J].Journal of Traditional Chinese Medicine,2003,4:5-7.
[30]葛朝亮,汪宁.通窍活血汤对血管性痴呆大鼠脑皮质中NO、ET-1、LPO含量的实验研究[J].安徽医药,2011,9：11-13.
[31]陈建鸿,杜建.益气解毒法治疗老年性痴呆的临床研究[J].福建中医学院学报,2006,5：9-10.
[32]邱昕,陈国华,冯佩,等.黄连解毒汤对APP/PS1双转基因AD小鼠海马区病理形态学及脑内β-APP基因mRNA的影响[J].神经损伤与功能重建,2010,5(6)：404-408.
[33]宋建芳,边宝林,王宏洁.黄连解毒汤治疗老年性痴呆药理研究进展[J].中国中医药信息杂志,2010,：17(5)：110-112.
[34]张晓杰.大鼠脑内注射Aβ1-40致海马损伤的炎症相关机制及通络救脑口 服液的作用[D].北京中医药大学,2008,2.
[35]张晓杰,牛英才,周丽,等.海马注射β-淀粉样蛋白对BACE1 mRNA的影响及通络救脑口服液的干预作用[J].中药药理与临床,2006,6：52-55.
[36]张晓杰,董海影,孙玉荣,等.大鼠大脑海马注射β-淀粉样蛋白对caspsae-3蛋白表达的影响及通络救脑口服液的干预作用[J].中华中医药杂志,2010,10：144-146.
[37]张晓杰,张静艳,赵坤,等.通络救脑口服液对AD大鼠海马单胺氧化酶活性、脂褐素含量的影响[J].中国老年学杂志,2010,18：78-80.
[38]张晓杰,董海影,李澎涛.通络救脑口服液对AD大鼠学习记忆能力及突触素蛋白表达的影响[J].北京中医药大学学报,2010,7：49-54.
[39]兴桂华,牛英才,张晓杰,等.通络救脑口服液对老年性痴呆模型大鼠海马区生长抑素、胆碱乙酰化酶表达的影响[J].中华中医药杂志,2008,4：96-98.
[40]董海影,张春庆,宫国良,等.通络救脑口服液对AD大鼠学习记忆能力及nNOS、SS表达的影响[J].时珍国医国药,2010,10：126-128.
[41]张晓杰,张春庆,胡南,等.Aβ1-40脑内注射对大鼠海马超氧化物歧化酶丙二醛的影响及通络救脑口服液的干预作用[J].时珍国医国药,2010,7：86-87.
[42]李小靓.通络救脑注射液对大鼠海马神经元的保护作用[D].北京中医药大学,2009,10.
[43]顾兆伟.通络救脑注射液治疗中风病(风火上扰、瘀血阻络证)的临床研究[D].长春中医药大学,2008,4.
[44]Rafii MS,Walsh S,Little JT,et al.A phase Ⅱ trial of huperzine A in mild to moderate Alzheimer disease[J].Neurology,2011,76(16):1389-1394.
[45]Pohanka M.Cholinesterases,a target of pharmacology and toxicology[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2011,155(3):219-229.
[46]Park P,Schachter S,Yaksh T.Intrathecal huperzine A increases thermal escape latency and decreases flinching behavior in the formalin test in rats[J].Neurosci Lett,2010,470(1):6-9.
[47]Zhang GR,Cheng XR,Zhou WX,et al.Age-related expression of calcium/calmodulin-dependent protein kinase Ⅱ A in the hippocampus and cerebral cortex of senescence accelerated mouse prone/8 mice is modulated by anti-Alzheimer's disease drugs[J].Neuroscience,2009,159(1):308-315.
[48]Shi J,Liu Q,Wang Y,et al.Coadministration of huperzine A and ligustrazine phosphate effectively reverses scopolamine-induced amnesia in rats[J].Pharmacol Biochem Behav,2010,96(4):449-453.
[49]Zoladz PR,Diamond DM.Linear and non-linear dose-response functions reveal a hormetic relationship between stress and learning[J].Dose Response, 2008,7(2):132-148.
[50]Hemendinger RA,Armstrong EJ 3rd,Persinski R,et al.Huperzine A provides neuroprotection against several cell death inducers using in vitro model systems of motor neuron cell death[J].Neurotox Res,2008,13(1):49-61.
[51]Park H,Oh MS.Houttuyniae Herba protects rat primary cortical cells from Aβ25-35-induced neurotoxicity via regulation of calcium influx and mitochondria-mediated apoptosis[J].Hum Exp Toxicol,2012 Jan 19.
[52]Eiden M,Leidel F,Strohmeier B,et al.A Medicinal Herb Scutellaria lateriflora Inhibits PrP Replication in vitro and Delays the Onset of Prion Disease in Mice[J].Front Psychiatry,2012,3:9.
[53]Xian YF,Lin ZX,Zhao M,et al.Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice[J].Planta Med,2011,77(18):1977-1983.
[54]Mei Z,Yan P,Situ B,et al.Cryptotanshinione Inhibits (3-Amyloid Aggregation and Protects Damage from (3-Amyloid in SH-SY5Y Cells[J].Neurochem Res, 2012,37(3):622-628.
[55]da Rocha MD,Viegas FP,Campos HC,et al.The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders Ⅱ:Alzheimer's disease[J].CNS Neurol Disord Drug Targets,2011,10(2):251-270.
[56]苏芮,韩振蕴,范吉平.阿尔茨海默病中医病因病机探讨[J].中华中医药杂志,2010,25(5)：743-744.
[57]贾树林.加减洗心汤治疗血管性痴呆30例临床观察[J].长春中医药大学学报,2011,3：90-91.
[58]赵建军.补肾健脾法治疗脑萎缩68例临床观察[J].中国现代药物应用,2007,8：52.
[59]郑丽,翟李娟.辨证分型治疗老年痴呆症30例疗效观察[J].河南中医学院学报.2004,4：54-55.
[60]吴虹.浅谈中医对老年性痴呆症的认识和防治[J].现代中西医结合杂志.2000,17：74-75.
[61]胡梅芳.老年性痴呆从肾虚痰瘀论治[J].浙江中医药大学学报,2009,33(3)：375-376.
[62]刘玲,董欢,姜幼明,等.涤痰汤对小鼠学习记忆功能障碍的影响[J].光明中医,2010,8：52-55.
[63]芦凤琴,闫伟.加味二陈汤治疗脑卒中后血管性痴呆40例[J].中国中医急症,2011,4：131-132.
[64]曹玉笈,刘珍华.益气活血化痰法治疗老年性痴呆症36例[J].国医论坛,2004,3：34.
[65]王辉,韩涛,张婷,等.化痰祛瘀治疗血管性认知功能障碍随机对照试验的Meta分析[J].中国实验方剂学杂志,2012,3：267-270.
[66]孔令海,孙金华.癫狂梦醒汤加减治疗老年性痴呆50例[J].中国医药导报,2009,16：137.
[67]张晶,张彪.还少丹加减治疗血管性痴呆54例[J].南京中医药大学学报,2008,6：70-71.
[68]张峰,贺林,朱晨,等.还少丹加减治疗血管性痴呆60例[J].光明中医,2011,8：72-73.
[69]龚梦娟,邹忠杰,谢媛媛.还少丹对记忆障碍模型小鼠空间学习记忆能力的影响[J].时珍国医国药,2011,8：114-115.
[70]李杰.金匮肾气丸加减治疗老年性痴呆的临床观察[J].中国医药指南,2010,29：272-273.
[71]赵振,赵力维.金匮肾气丸加味治疗老年轻度认知功能障碍临床观察[J].吉林中医药,2009,7：35-36.
[72]何慧,张玉莲,崔远武,等.老年性痴呆中医治则治法规律研究[J].吉林中医药,2012,2：23-25.
[73]Sun M,Zhou T,Zhou L,et al.Formononetin Protects Neurons Against Hypoxia-Induced Cytotoxicity Through Upregulation of ADAM10 and sApPPa[J].J Alzheimers Dis,2012,28(4):795-808.
[74]魏永吾,王红.辩证治疗老年痴呆50例[J].陕西中医,2009,7：53-54.
[75]田旭升,安平.左归丸对痴呆鼠氧化反应及细胞凋亡的影响[J].时珍国医国药,2007,12：65-66.
[76]徐光华.补肝肾活血通窍中药治疗老年性痴呆40例疗效观察[J].医学信息,2010,5：239-240.
[77]卢昕,芦霜,陈民.用“补肾祛痰化瘀”法辨证施护老年痴呆的研究[J].中华中医药学刊,2009,5：120-121.
[78]于晓宁.补肾活血化痰法治疗老年性痴呆42例临床观察[J].中医药导报,2006,2：32-33.
[79]Yang DY,Wang XZ.Gu Sui Bu(Rhizoma Drynariae)—A Good Drug for Senile Dementia[J].Journal of Traditional Chinese Medicine,2005,4:52-53.
[80]黄启辉,魏昌秀.李庆明教授对老年痴呆病因病机的认识及其辨证分型[J].中医药学刊,2003,21(5)：647.
[81]胡九东,王嘉敏.补肾泻浊治疗老年性痴呆30例[J].中国临床医生,1999,2：49.
[82]胡慧,王平,孔明望,等.补肾化痰方药对阿尔茨海默病模型大鼠脑组织钙/钙调素依赖的蛋白激酶Ⅱ-α活性的影响[J].中华中医药杂志,2010,25(5)：149-151.
[83]梅静,刘春光,孙利.针灸治疗老年性痴呆76例[J].中国民间疗法,2003,11(12)：14-15.
[84]吴迪.针灸治疗早老性痴呆36例[J].四川中医,2004,3：94-95.
[85]董洪涛,白英.针刺疗法对老年性痴呆患者MMSE量表得分的影响.中医外治杂志,2002,11(3)：6-7.
[86]唐勇,余曙光,陈瑾,等.针刺对老年性痴呆认知功能及AChE的影响.上海针灸杂志,2001,20(3)：6-7.
[87]戴思思,董克礼,朱宏.“补肾活血”针刺法对老年性痴呆模型SAMP8小鼠学习记忆能力和脑组织AChE活性的影响[J].上海针灸杂志,2010,29(1)：57-59.
[88]杨定荣,彭力,穆敬平,等.针刺结合穴位注射治疗老年痴呆临床观察[J].中国康复理论与实践,2008,14(1)：81.
[89]马梅青.安神醒脑汤配合针灸治疗老年性痴呆56例[J].陕西中医,2003,8：30-31.
[90]Ho YS,So KF,Chang RC.Drug discovery from Chinese medicine against neurodegeneration in Alzheimer's and vascular dementia[J].Chin Med,2011,6:15.
[1]Debby Van Dam,Peter Paul De Deyn. Drug discovery in dementia:the role of rodent models[J].Nat Rev Drug Discov,2006,Nov;5(11):956-970.
[2]Toshio Takeda.Senescence-accelerated mouse (SAM) with special references to neurodegeneration models,SAMP8 and SAMP10 mice[J].Neurochem Res,2009, 34:639-659.
[3]Koji Tomobe,Yasuyuki Nomura.Neurochemistry,neuropathology,and heredity in SAMP8:A mouse model of senescence[J].Neurochem Res,2009,34:660-669.
[4]Yasunobu Okuma,Yasuyuki Nomura.Senescence-accelerated mouse (SAM) as an animal model of senile dementia:pharmacological,neurochemical and molecular biological approach[J].Jpn.J.Pharmacol,1998,78:399-404.
[5]Kumar VB,Franko M,Banks WA,et al.Increase in Presenilin 1(PS1) levels in senescence-accelerated mice(SAMP8) may indirectly impair memory by affecting amyloid precursor protein(APP) processing[J].J Experimental Biology,2009, 212:494-498.
[6]Kim BH,Meeker HC,Shin HY,et al.Physiological properties of astroglial cell lines derived from mice with high (SAMP8) and low (SAMR1,ICR) levels of endogenous retro virus [J].Retro virology,2008,5:104.
[7]Pang KC,Miller JP,Fortress A,et al.Age-related disruptions of circadian rhythm and memory in the senescence-accelerated mouse (SAMP8)[J].Age (Dordr), 2006,28(3):283-296.
[8]Cheng XR,Yang Y,Zhou WX,et al.Expression of VGLUTs contributes to degeneration and acquisition of learning and memory[J].Neurobiol Learn Mem,2011,95(3):361-375.
[9]Spangler EL,Patel N,Speer D,et al.Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM):age and strain comparisons of SAM P8 and R1 [J].J Gerontol A Biol Sci Med Sci,2002,57(2):B61-68.
[10]Strong R.Reddy V,Morley JE.Cholinergic deficits in the septal-hippocampal pathway of the SAM-P/8 senescence accelerated mouse[J].Brain Res,2003, 966(1):150-156.
[11]Morley JE,Kumar VB,Bernardo AE,et al.p-Amyloid precursor polypeptide in SAMP8 mice affects learning and memory[J].Peptides,2000,21 (12):1761-1767.
[12]Kumar VB,Farr SA,Flood JF,et al.Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice[J].Peptides,2000,21(12):1769-1775.
[13]Pelegri C,Canudas AM,del Valle J,et al.Increased permeability of blood-brain barrier on the hippocampus of a murine model of senescence[J].Mech Ageing Dev,2007,128(9):522-528.
[14]Zhu Y,Lee CC,Lam WP,et al.Cell death in the Purkinje cells of the cerebellum of senescence accelerated mouse (SAMP(8))[J].Biogerontology,2007,8(5):537-544.
[15]施晓芸,陈晓春,石艳清,等.快速老化小鼠P8肾脏衰老的病理特点[J].中国老年学杂志,2010,3：43-45.
[16]Liu Y,He J,Ji S,et al.Comparative studies of early liver dysfunction in senescence-accelerated mouse using mitochondrial proteomics approaches[J].Mol Cell Proteomics,2008,7(9):1737-1747.
[17]Rebrin I,Zicoker S,Wedekind KJ,et al.Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse[J].Free Radic Biol Med,2005,39(4):549-557.
[18]Gutierrez-Cuesta J,Sureda FX,Romeu M.et al.Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8[J].J Pineal Res,2007,42(4):394-402.
[19]Chen CC,Liu MH,Wang MF,et al.Effects of aging and dietary antler supplementation on the calcium-regulating hormones and bone status in ovariectomized SAMP8 mice[J].Chin J Physiol,2007,50(6):308-314.
[20]Yang S,Qiao H,Wen L,et al.D-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8[J].Neurosci Lett,2005,379(1):7-12.
[21]唐勇,郭玲玲,张琪,等.快速老化小鼠肾脏组织-1H-NMR谱图变化及电针对其的影响[J].成都中医药大学学报,2009,2：3-6.
[22]蒋宁,周文霞,张永祥.应用代谢组学方法研究比较六味及八味地黄汤的作用机理[J].中药药理与临床,2007,5：45.
[23]朱宏,董克礼,李广成.“补肾活血”针刺法对SAMP8小鼠海马蛋白质表达的影响[J].中国老年学杂志,2011,31(23)：4613-4616.
[24]Wang Q,Matsumoto Y,Shindo T,et al.Neural stem cells transplantation in cortex in a mouse model of Alzheimer's disease[J].J Med Invest,2006, 53(1-2):61-69.
[25]Wang D,Noda Y,Zhou Y,et al.The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice:involvement of dopaminergic systems[J].Neuropsychopharmacology,2007,32(6):1261-1271.
[26]Prediger RD,Franco JL,Pandolfo P,et al.Differential susceptibility following β-amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice: Evidence for a dissociation between cognitive deficits and the glutathione system response[J].Behav Brain Res,2007,177:205-213.
[27]Bagheri M,Joghataei MT,Mohseni S,et al.Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's disease[J]. Neurobiol Learn Mem,2011,95(3):270-276.
[28]Alessandro Biffi,Steven M.Greenberg.Cerebral amyloid angiopathy:A systematic review[J].J Clin Neurol 2011;7:1-9.
[29]Gouras GK,Tampellini D,Takahashi RH,et al.Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease[J].Acta Neuropathol, 2010,119(5):523-541.
[30]Hernandez F,de Barreda EG,Fuster-Matanzo A,et al.The role of GSK3 in Alzheimer disease[J].Brain Res Bull,2009,80(4-5):248-250.
[31]Malm T,Ort M,Tahtivaara L,et al.beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits[J].Proc Natl Acad Sci U S A,2006,103(23):8852-8857.
[32]Lee JW,Lee YK,Yuk DY,et al.Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation[J].J Neuroinflammation,2008,5:37.
[33]原淑娟,张志雄,吴定宗,等.D-半乳糖对大鼠空间学习记忆行为与脑海马结构电生理以及突触形态学的影响[J].中国临床康复,2005,37：184-187.
[34]Medeiros R,Prediger RD,Passos GF,et al.Connecting TNF-α signaling pathways to iNOS expression in a mouse model of Alzheimer's disease:relevance for the behavioral and synaptic deficits induced by amyloid β protein[J].J Neurosci,2007,27(20):5394-5404.
[35]Watanabe T,Iwasaki K,Ishikane S,et al.Spatial memory impairment without apoptosis induced by the combination of Beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats[J].J Pharmacol Sci,2008,106:84-91.
[36]Bales KR,Liu F,Wu S,et al.Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice[J].J Neurosci,2009, 29(21):6771-6779.
[37]Ray S,Howells C,Eaton ED,et al.Tg2576 cortical neurons that express human Ab are susceptible to extracellular Aβ-induced,K+efflux dependent neurodegeneration[J].PLoS One,2011,6(4):e 19026.
[38]Middei S,Roberto A,Berretta N,et al.Learning discloses abnormal structural and functional plasticity at hippocampal synapses in the APP23 mouse model of Alzheimer's disease[J].Learn Mem,2010,17(5):236-240.
[39]Yang DS,Stavrides P,Mohan PS,et al.Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits[J].Brain,2011,134(Pt 1):258-277.
[40]Duyckaerts C,Potier MC,Delatour B.Alzheimer disease models and human neuropathology:similarities and differences[J].Acta Neuropathol,2008, 115(1):5-38.
[41]Bien-Ly N,Andrews-Zwilling Y,Xu Q,et al.C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice.[J].Proc Natl Acad Sci U S A,2011,108(10):4236-4241.
[42]Clinton LK,Billings LM,Green KN,et al.Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice[J].Neurobiol Dis,2007, 28(1):76-82.
[1]Christian Humpel.Chronic mild cerebrovascular dysfunction as a cause for Alzheimer's disease[J]? Exp Gerontol,2011,46(4):225-232.
[2]Alzheimer's Association,Thies W,Bleiler L.2011 Alzheimer's disease facts and figures[J].Alzheimers Dement,2011,7(2):208-244.
[3]Berislav V.Zlokovic.Neurovascular mechanisms of Alzheimer's neurodegeneration[J].Neuro sciences.2005, April,28(4):202-208.
[1]R.D.S.Prediger,R.Medeiros,P.Pandolfo,et al.Genetic deletion or antagonism of Kinin Bl and B2 receptors improves cognitive deficits in a mouse model of Alzheimer's disease[J].Neuroscience,2008,151:631-643.
[2]George Paxinos Keith B.J.Franklin.The mouse brain[M].Academic Press,2001,50.
[3]Alberto E.Musto,Mark S.Samii,Justin F.Hayes.Different phases of afterdischarge during rapid kindling procedure in mice[J].Epilepsy Res,2009,85(2-3):199-205.
[4]Jerry J Buccafusco.Methods of Behavior Analysis in Neuroscience[M].Boca Raton (FL):CRC Press,2009,6.
[5]Rodrigo Medeiros,Rui D.S.Prediger,Giselle F.Passos.et al.Connecting TNF-α signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid (3 protein[J].The Journal of Neuroscience,2007,27(20):5394-5404.
[6]Tomobe K,Nomura Y.Neurochemistry,neuropathology,and heredity in SAMP8: a mouse model of senescence[J].Neurochem Res,2009,34(4):660-669.
[7]Tajes M,Gutierrez-Cuesta J,Folch J,et al.Neuroprotective role of intermittent fasting in senescence-accelerated mice P8 (SAMP8) [J].Exp Gerontol, 2010,45(9):702-710.
[1]Parihar MS,Brewer GJ.Amyloid Beta as a Modulator of Synaptic Plasticity[J].J Alzheimers Dis,2010,22(3):741-763.
[2]Seeman P,Seeman N.Alzheimer's Disease:β-Amyloid Plaque Formation in Human Brain[J].Synapse,2011,65(12):1289-1297.
[3]Manich G,Mercader C,del Valle J,et al.Characterization of amyloid-β granules in the hippocampus of SAMP8 mice[J].J Alzheimers Dis,2011,25(3):535-546.
[4]Zheng H,Koo EH.The amyloid precursor protein:beyond amyloid[J].Mol Neurodegener,2006,1:5.
[5]O'Brien RJ.Wong PC.Amyloid Precursor Protein Processing and Alzheimer's Disease[J].Annu Rev Neurosci,2011,34:185-204.
[6]Bateman RJ,Klunk WE.Measuring target effect of proposed disease-modifying therapies in Alzheimer's disease[J].Neurotherapeutics,2008,5(3):381-390.
[7]Kumar VB,Franko M,Banks WA,et al.Increase in presenilin 1 (PS1) levels in senescence-accelerated mice (SAMP8) may indirectly impair memory by affecting amyloid precursor protein (APP) processing[J].J Exp Biol,2009,212(Pt 4):494-498.
[8]Niikura T,Sidahmed E,Hirata-Fukae C,et al.A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice[J].PLoS One,2011,6(1):e 16259.
[9]Laibaik Parka,Gang Wanga,Ping Zhou,et al.Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β[J].Proc Natl Acad Sci U S A,2011,108(12):5063-5068.
[10]Magdalena Sastre,Jochen Walter,Steve M Gentleman,et al.Interactions between APP secretases and inflammatory mediators[J].J Neuroinflammation. 2008,18(5):25-35.
[11]Koji Tomobe,Yasuyuki Nomura.Neurochemistry,neuropathology,and heredity in SAMP8:a mouse model of senescence[J].Neurochem Res,2009,34:660-669.
[12]Ahmed RR,Holler CJ,Webb RL,et al.BACE1 and BACE2 enzymatic activities in Alzheimer's disease[J].J Neurochem,2010,112(4):1045-1053.
[13]Colciaghi F,Marcello E,Borroni B,et al.Platelet APP,ADAM 10 and BACE alterations in the early stages of Alzheimer disease[J]. Neurology,2004. 62(3):498-501.
[14]Venugopal C,Demos CM,Rao KS,et al.Beta-secretase:structure,function,and evolution[J].CNS Neurol Disord Drug Targets,2008,7(3):278-294.
[15]Sato N,Ueki A,Ueno H,et al.IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type[J].Curr Gerontol Geriatr Res,2008:858759.
[16]Dorfman VB,Pasquini L,Riudavets M,et al.Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease[J].Neurobiol Aging,2010,31(10):1743-1757.
[17]de Tullio MB,Morelli L,Castano EM.The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme:a biological perspective[J]. Prion.2008 Apr-Jun;2(2):51-6.
[18]Kim MS,Goo JS,Kim JE,et al.Overexpression of Insulin Degrading Enzyme could Greatly Contribute to Insulin Down-regulation Induced by Short-Term Swimming Exercise[J].Lab Anim Res,2011,27(1):29-36.
[19]Neant-Fery M,Garcia-Ordonez RD,Logan TP,et al.Molecular basis for the thiol sensitivity of insulin-degrading enzyme.[J].Proc Natl Acad Sci U S A,2008,105(28):9582-9587.
[20]Vepslinen S,Hiltunen M,Helisalmi S,et al.Increased expression of Abeta degrading enzyme IDE in the cortex of transgenic mice with Alzheimer's disease-like neuropathology[J].Neurosci Lett,2008,438(2):216-220.
[21]May P,Rohlmann A,Bock HH,et al.Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice[J].Mol Cell Biol,2004,24(20):8872-8883.
[22]Meijer AB,Rohlena J,van der Zwaan C,et al.Functional duplication of ligand-binding domains within low-density lipoprotein receptor-related protein for interaction with receptor associated protein,alpha2-macroglobulin,factor IXa and factor VIII[J].Biochim Biophys Acta,2007,1774(6):714-722.
[23]Deane R,Wu Z,Sagare A,et al.LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms[J].Neuron,2004,43(3):333-344.
[24]Robert D.Bell,Abhay Sagare.Alan E.Friedman,et al.Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system[J].J Cereb Blood Flow Metab,2007, 27(5):909-918.
[25]Rashid Deane,Zhenhua Wu.Berislav V.Zlokovic.RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier[J].Stroke,2004,35:2628-2631.
[26]Donahue JE,Flaherty SL,Johanson CE,et al.RAGE,LRP-1,and amyloid-beta protein in Alzheimer's disease[J].Acta Neuropathol,2006,112:405-415.
[27]Han SH,Kim YH,Inhee MJ.RAGE:The Beneficial and Deleterious Effects by Diverse Mechanisms of Actions[J].Mol Cells,2011,31:91-97.
[28]Kandimalla KK,Curran GL,Holasek SS,et al.Pharmacokinetic analysis of the blood-brain barrier transport of 1251-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation[J].J Pharmacol Exp Ther,2005,313(3):1370-1378.
[29]Qiang Liu,Celina V.Zerbinattil,Juan Zhang,et al.Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1 [J].Neuron,2007,56(1):66-78.
[30]Mielke MM,Leoutsakos JM,Tschanz JT,et al.Interaction between vascular factors and the APOE ε4 allele in predicting rate of progression in Alzheimer's disease[J].J Alzheimers Dis,2011,26(1):127-134.
[31]Tai LM,Youmans KL,Jungbauer L,et al.Introducing Human APOE into A[3 Transgenic Mouse Models[J].Int J Alzheimers Dis,2011,2011:810981.
[32]Anna P.Lillis,Lauren B.Van Duyn,Joanne E.Murphy-Ullrich,et al.The low density lipoprotein receptor-related protein 1:Unique tissue-specific functions revealed by selective gene knockout studies[J].Physiol Rev,2008,88(3):887-918.
[33]Yoshiike Y,Minai R,Matsuo Y,et al.Amyloid oligomer conformation in a group of natively folded proteins[J].PLoS One,2008,3(9):e3235.
[34]Edwards TL,Pericak-Vance M,Gilbert JR,et al.An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE,A2M,and LRRTM3[J].Am J Med Genet B Neuropsychiatr Genet.2009 Jul 5;150B(5):721-35.