肠源性内毒素血症在阿尔茨海默病发病中作用及相关机制研究
|
摘要
老年性痴呆是一种慢性进行性精神衰退性疾病,临床表现以痴呆症状最为突出,病理改变以大脑的萎缩和变性为主。临床上主要包括阿尔茨海默型痴呆(Alzheimer's Disease,AD)、脑血管性痴呆(VascularDementia,VD)和其他混合痴呆等,是世界范围内严重影响老年人健康的常见病、多发病。以往认为欧美国家人群中的痴呆患者以AD为主,亚洲国家则以VD为主。我国几个城市普查60岁以上老年人中,VD为人口的324/10万,AD为328/10万。1990年张明远等与美国几家科研单位合作流行病学调查发现,上海在55岁以上痴呆患者中,AD占64.7%,VD占26.8%。说明在我国至少在某些地区AD在痴呆患者中占主要地位。而AD防治的最大障碍是病因未明。
AD在65岁以上的老年人有11%、80岁以上有50%会出现病症。其主要特征为智力的损伤,包括学习记忆、语言、读写、行为,以及对周围环境的识别,最终可导致死亡。其病理改变为弥漫性脑萎缩,以颞叶前、中部及海马、顶叶及前额叶区的萎缩最明显,脑室扩大,脑回变窄、脑沟加宽、脑裂加大;显微镜下可见神经原纤维缠结(NFT),老年斑(SPs)和颗粒空泡变性比健康老年人明显增多。多年来对AD的病因做了大量的研究,但迄今为止,病因仍不明,确切的致病因素并未找到。因为病因极其复杂,有患者自身的生物学因素,也有多种环境与社会因素的影响。
在AD发病机制的众多假说中,炎症机制假说占有重要的地位,大量的研究证明在AD发生过程中脑内有大量的炎性因子,如白介素-1(IL-1)、肿瘤坏死因子(tumor necrosisfactor-α,TNF-α)、白介素-6(IL-6)、转化生长因子β(Transforming Growth factorβ,TGF-β)、环氧化酶-2(Cyclooxygenase-2,COX-2)、补体及急性期反应蛋白的分泌。这些炎性因子通过一系列的信号转导途径,如NF-κB、丝裂原激活蛋白激酶((mitogen-αctivated proteinkinase,MAPK)途径激活神经小胶质细胞(microglia,MG)和星形细胞(astrocyte,AC),使之释放更多的炎性因子,同时它们又共同参与了脑局部炎症过程,与淀粉样蛋白(βamyloid,Aβ)和Tau蛋白的沉积紧密相关,这些研究确定了局部炎症在AD的病理生理过程中发挥了重要作用,甚至有的作者将炎症同SP和NFT共同并列为AD的3大主要特征。
韩德五教授于1995年首次提出的肝功能衰竭发生机制的肠源性内毒素血症(Intestinalendotoxemia,IETM)假说认为肠源性内毒素激活枯否细胞所分泌的多种活性物质(如细胞因子、炎性介质、自由基等)可引起“继发性肝损伤”,是导致多种急慢性肝病演化为肝功能衰竭发生的重要机制之一。大量的实验及临床研究证明,不但肝脏疾患伴有IETM,烫伤、烧伤、创伤、出血性休克、急性胰腺炎等多种疾病也伴有IETM。
在IETM中发挥核心作用的内毒素是革兰氏阴性杆菌细胞壁外膜表层构成成份,是脂多糖(LPS)与蛋白的复合体,是体内巨噬细胞最敏感的激活剂。正常肠道中含有大量的细菌和内毒素,生理状态下由于肠粘膜屏障的保护作用,肠腔中存在的内毒素只有极少量进入外周循环,对机体维持一定的免疫力可能有意义;同时肝脏的枯否细胞也会吞噬清除血液中过多的内毒素,防止IETM的发生。但是,当机体受到严重创伤(包括手术)、烧伤、放化疗和长期传统的肠外营养时,肠粘膜有可能发生通透性增高;或枯否细胞吞噬活性严重下降,对血浆中内毒素清除能力下降时,就有可能导致细菌及内毒素移位,引起内源性感染,甚至多脏器功能衰竭(MOF)。
内毒素是到目前为止已知的诱导IL-1、TNF-α等最重要的因子,可以充分激活巨噬细胞,释放大量炎症因子,激活细胞因子级联反应:
1、枯否细胞活化后可生成和释放TNF-α、IL-1、IL-6、血小板激活因子(platelet-activatedfactor,PAF)、PGs等细胞因之的分泌,损伤肝细胞;枯否细胞活化后所释放的白三烯,特别是LT-B_4具有强烈的化学趋化作用,吸引并激活中性粒细胞,产生并释放自由基,使细胞膜和细胞器膜发生脂质过氧化而损伤细胞。
2、枯否细胞活化后生成和释放的活性氧中间产物(ROI)可引发脂质过氧化反应,损伤生物膜系统、核酸和蛋白质导致肝细胞死亡。
3、枯否细胞与肝窦内皮细胞是花生四烯酸特别是PGD_2、PGE_2及血栓素的重要来源,可经对应的受体作用于肝细胞,引起蛋白磷酸化及膜稳定性变化。
通过以上机制,IETM会导致全身炎症反应综合症(SIRS)、多器官功能不全(MOD),甚至多器官功能衰竭(MOF)。
综上所述,IETM会导致机体发生严重的SIRS,而局部炎症在AD的病理生理过程中发挥了重要作用。那么同样高发于老年人的IETM与AD二者之间有何联系?IETM会不会是AD发病的一个危险因素?IETM在AD发病过程中有何作用?目前尚未见到相关报道,为此,我们设计了本次课题研究研究计划。
本研究由以下三个部分组成:
第一部分D-半乳糖和三氯化铝建立的AD大鼠模型的研究
实验目的及背景
关于AD的发病机制目前有胆碱能学说、基因突变和多态性学说、自身免疫学说、能量代谢障碍学说等。目前,依据各种学说已建立了多种AD动物模型,但每种模型均有一定的局限性,不能全面模拟AD的病理特征。为了建立一种准确可靠的AD模型,我们进行了本次实验,以期为AD研究提供一种新的大鼠模型。
大量研究表明,铝元素具有剂量与作用时间依赖性的诱导动物脑内发生病理变化,具有明显的神经毒作用,可引起明显的学习及记忆减退。D-半乳糖能较好的模拟小鼠的衰老表现,使小鼠机体出现与自然衰老相似的代谢紊乱特征,还引起脑神经元的一系列退行性改变,但腹腔注射D-半乳糖和AlCl_3制备阿尔茨海默病大鼠模型的报道还未见到。
实验方法
1、AD模型制备:模型组腹腔注射D-半乳糖60mg·kg~(-1)·d~(-1)(生理盐水配制,60g/L,给药量0.2ml/200g)和AlCl_3 25mg·kg~(-1)·d~(-1)(双蒸水配制,25g/L,给药量0.2ml/200g),连续90天;空白对照组腹腔注射等量的生理盐水和等量的双蒸水。
2、Morris水迷宫行为学实验
2.1定位航行实验水池分为N、E、S、W 4个象限。实验前1d将大鼠放入水池(不含平台)自由游泳2 min熟悉水迷宫环境,试验历时5d,每天分上午(n-1),下午(n-2)两个时间段,每段分别训练4次。训练开始时将平台置于SW象限,每个时间段分别从池壁4个起始点将大鼠面向池壁放入水池,记录每次找到平台的时间(逃避潜伏期,escape latency)和游泳路径。如大鼠在120s内找不到平台,由实验者将其引上平台,潜伏期记为120s,并记录为1次寻找站台错误,每次间隔4min让大鼠休息,再行下次试验。
2.2空间探索实验在第5天下午第5次训练时拆除水下平台,然后任选一个入水点将大鼠面向池壁放入水中,测其120s内在各象限的游泳距离及占总距离的百分率和120 s内跨越各象限平台相应位置次数及占总次数的百分率,并记录大鼠120s内搜索平台的路线图。
3、大鼠脑组织总蛋白(TP)、组织过氧化物酶(POD)、总抗氧化能力(T-AOC)、胆碱乙酰转移酶(ChAT)、胆碱酯酶(ChE)、一氧化氮(NO)、一氧化氮合酶(NOS)测定:取各组大鼠脑组织,分析天平称湿重,按脑组织:生理盐水0.2g:1.8ml比例制成10%脑组织匀浆,3000r/min,离心15min,取上清液,冻存待测。TP、POD、T-AOC、ChAT、ChE、NOS、NO试剂盒由南京建成生物制品有限公司提供,严格按照操作说明进行操作。
4、大鼠脑组织Tau蛋白浓度检测:双抗体夹心式酶联免疫吸附法(ELISA)。
5、大鼠脑组织凋亡测定:TUNEL法与流式细胞仪检测。
6、大鼠脑组织电镜观察:大鼠脑组织切成1mm~3大小的组织块,经2%二甲砷酸钠缓冲戊二醛和1%锇酸双固定,丙酮脱水,包埋,制成超薄切片,在JEM 100CX型透射电镜下观察脑组织的改变。
7、大鼠脑组织Aβ1-40检测:免疫组织化学法。
8、大鼠脑组织APP、PS1和BACE mRNA检测:两步法半定量逆转录聚合酶链反应(RT-PCR)技术检测。
实验结果
本部分实验通过给大鼠腹腔注射D-半乳糖和AlCl_3,不但复制出大鼠整体衰老过程、学习记忆力减退、脑组织ChAT活性降低、ChE活性升高所致乙酰胆碱能系统活性降低,脑组织抗氧化能力降低及NO系统活性增高等AD特征性的变化。同时,AD大鼠脑组织内APP、PS1、BACE mRNA表达增强、出现Aβ沉积、Tau蛋白含量增高、脑细胞凋亡、老年斑等AD的特征性病理变化。
实验结论
腹腔注射D-半乳糖和AlCl_3可以成功制备阿尔茨海默病模型,为AD的研究提供了一种新的大鼠模型。
第二部分IETM在AD模型发病中相关机制研究
实验目的及背景
IETM假说是韩德五教授于1995年首次提出的肝功能衰竭发生的机制。在IETM中发挥核心作用的内毒素可以激活枯否细胞分泌多种活性物质(如细胞因子、炎性介质、自由基等),可引起“继发性肝损伤”,甚至会导致全身炎症反应综合症(SIRS)、多器官功能不全(MOD),甚至多器官功能衰竭(MOF)的发生。大量的实验及临床研究证明,在烫伤、烧伤、创伤、出血性休克、急性胰腺炎等多种疾病也有IETM的发生。Goto等的研究表明337名72岁的老年人中有21.5%的老年人血浆内毒素水平高于正常,可见即使在正常人,IETM水平也随着年龄增长在逐渐升高。
炎症机制假说在AD发病机制的众多假说中占有重要的地位,大量的研究证明在AD发生过程中脑内有大量的炎性因子,如TNF-α、IL-1、IL-6、TGF-β、COX-2、补体及急性期反应蛋白的分泌。这些炎性因子通过一系列的信号转道途径,如NF-KB、MAPK途径激活神经MG和AC,使之释放更多的炎性因子,同时它们又共同参与了脑局部炎症过程,与Aβ和Tau蛋白的沉积紧密相关,这些研究确定了局部炎症在AD的病理生理过程中发挥了重要作用。
在我们所制备的AD模型体内是否也出现了IETM?如果是,IETM与AD二者之间有无内在的联系?IETM是否参与了AD的发病过程?IETM会不会是AD发病的一个危险因素?目前尚未见相关报道,为此我们进行了第二部分实验。
实验方法
1、血浆LPS、TNF-α、IL-1β及IL-10测定:采用改良过氯酸法检测血浆LPS含量,鲎试剂盒由上海医学化验所提供;放射免疫分析法测定血浆中TNF-α、IL-1β及IL-10含量,试剂盒由解放军总医院东亚免疫研究所提供。
2、大鼠肝脏枯否细胞功能状态检测:免疫组织化学SABC染色法检测肝组织溶菌酶LYZ阳性细胞-KC的数量和形态。
3、二胺氧化酶(Diamine oxidase,DAO)、谷氨酰胺(Glutamine,Gln)及谷氨酰胺酶(Glutaminase)活性检测:DAO采用黎君友等分光光度计法,谷氨酰胺采用酚一次氯酸法检测,谷氨酰胺酶活性采用荧光法测定。
4、肠粘膜常规HE染色,光镜下观察粘膜结构变化。
5、大鼠血清S-100β测定:双抗体夹心式酶联免疫吸附法(ELISA),试剂盒购自上海森雄生物科技有限公司。
6、大鼠脑组织ZO-1蛋白检测:免疫印迹法(Western blot)。
实验结果
腹腔注射D-半乳糖和AlCl_3制备的AD模型大鼠血浆中LPS、TNF-α、IL-1β及IL-10含量均明显升高,与对照组比较有统计学差异(P＜0.01);肝组织KC数量减少,吞噬LPS功能减弱;肠粘膜及血脑屏障通透性均明显升高,屏障功能明显下降。
实验结论
腹腔注射D-半乳糖和AlCl_3制备的AD模型大鼠KC吞噬功能、肠粘膜屏障及血脑屏障功能均明显下降,血浆中LPS及TNF-α、IL-1β等炎症因子含量增高,AD大鼠体内出现了IETM。
第三部分LPS激活BV-2细胞及其分子机制的研究
研究目的及背景
脑内炎症在AD、帕金森病等慢性神经变性疾病发病机理上发挥着重要作用。作为脑内固有免疫细胞的MG在AD发病中的急性与慢性神经炎症过程中均担当了重要的角色。
MG被激活后产生释放大量的前体炎症因子,可以产生细胞毒性因子(蛋白水解酶、细胞因子、兴奋性氨基酸、毗啶、2,3-二羧酸、补体蛋白、活性氧媒介物、一氧化氮等),Seabrook等的实验证明脑内炎症和MG有着密切关系,LPS诱导MG激活产生炎性细胞因子TNF-α、IL-1、IL-6,其信号转导途径有PTK途径、磷酸脂酶A_2(PLA_2)途径,还与细胞内核转录因子NF-κB、CREB等的活化有关。
有研究表明,Aβ在AD发病中的毒性作用机制可能与其扰乱细胞内钙稳态、产生活性氧和自由基、增加兴奋性毒性等作用有关。
我们通过体外培养BV-2细胞来研究在IETM中发挥核心致病作用的LPS对MG的激活作用、MG激活后释放的炎症因子在AD发病中的作用及其具体机制,从而进一步揭示IETM在AD发病中的作用及其机制。
实验方法
1、BV-2细胞培养:BV-2细胞株购自中国医科院协和医科大学基础医学细胞中心。含体积分数为0.1的胎牛血清的DMEM高糖培养基加青霉素100u/ml、链霉素100u/ml,置37℃、体积分数为0.05的CO_2的培养箱内培养,每隔1d换1次培养液,三四天传代1次。每次实验前细胞在含有10g/L牛血清白蛋白的DMEM培养基中培养48h后使细胞处于同步化状态。
2、BV-2细胞分组:BV-2(阴性对照组);BV-2+Aβ:30min、1h、3h、6h、12h、24h组;BV-2+LPS:30min、1h、3h、6h、12h、24h组。分别加入含有LPS(100ng/ml)、Aβ(20μg/ml)的培养基,培养30min、1h、3h、6h、12h、24h后,进行以下实验项目,每个处理组每个时间点观察6片。
3、BV-2细胞形态学观察:取对数生长期BV-2细胞接种于6孔培养板中(密度为2×10~5/孔),每组设3个平行孔,倒置显微镜下观察BV-2细胞形态,拍照。
4、BV-2细胞吞噬功能定量测定:参考Hirose的方法进行,细胞培养皿(10~4个细胞/片/皿)中加入聚苯乙烯乳珠0.5×10~8个,培养30min、1h、3h、6h、12h、24h后,PBS洗三次,洗去未被吞噬聚苯乙烯乳珠,直接倒置显微镜下对细胞所吞噬聚苯乙烯乳珠进行计数,观察,照像。每皿任取5个视野,每个视野随机数20个BV-2进行计数,取细胞吞噬聚苯乙烯乳珠数的平均值代表该皿细胞的吞噬功能。
5、BV-2细胞OX-42检测:免疫荧光法。Aβ1-40与LPS分别作用30min、1h、3h、6h、12h、24h后终止细胞培养,PBS清洗3次,丙酮室温固定,3%过氧化氢-甲醇室温下10min,正常山羊封闭血清,室温下孵育20min,滴加一抗5μl(小鼠抗大鼠OX-421:100),湿盒内37℃孵育2h,二抗(FITC),室温1h,倒置显微镜观察拍照。每皿任取5个视野,取每个视野OX-42阳性表达细胞数及荧光强度代表该皿细胞的活性。
6、BV-2细胞培养上清液TNF-α、IL-1β测定:双抗体夹心式酶联免疫吸附法(ELISA)。
7、BV-2细胞凋亡检测:各组细胞用PBS制成细胞悬液,不低于1×10~6个细胞/管,20%冰乙醇固定,轻轻混匀,PBS洗1次,重悬于500μlPBS后流式细胞仪检测。
8、BV-2细胞p38、JNK、NF-κB蛋白表达水平检测:免疫印迹法(Western blot)。
9、BV-2细胞[Ca~(2+)]i变化检测:按实验要求培养的BV-2,加入终浓度为10μmol/L的Fluo-3/AM,37℃负载40min,置于MRC-1024型共聚焦显微镜下,488nm激发波长,522nm发射波长扫描。细胞游离[Ca~(2+)]i动态测定:选定待测BV-2细胞后,先预扫4min获得基线值,继续扫描至4min时分别各自快速加入LPS 100ng/ml和Aβ1-40 20μg/ml观察荧光值的变化,用随机附带的Time-course/Rationmetric软件给出加药前后神经元内荧光值随时间变化的曲线。每皿取5个视野,每个视野随机选取10个BV-2细胞进行荧光值统计。荧光值强度代表[Ca~(2+)]i的浓度。
实验结果
Aβ1-40与LPS均可以激活BV-2细胞,使其形态发生明显变化,吞噬能力增强,OX-42表达增强,TNF-α、IL-1β分泌增多,凋亡率较对照组明显升高(P＜0.01),p-p38、p-JNK及NF-κB表达水平均明显高于对照组,[Ca~(2+)]i明显升高。
实验结论
LPS可以通过p38、JNK、NF-κB信号转导通路迅速激活BV-2细胞,提高其吞噬能力,促进其分泌炎症因子;而且,LPS对BV-2细胞还有促凋亡作用,并可以使BV-2细胞钙稳态失衡,发生钙超载。
LPS对BV-2的这种激活作用与Aβ1-40相似,可见LPS在AD的发病中发挥了与Aβ1-40类似的致病作用。
通过以上三部分研究,我们可以得出以下结论:
1、腹腔注射D-半乳糖和AlCl_3可以成功制备AD大鼠模型。
2、AD模型大鼠血浆中LPS及炎症因子水平升高,枯否细胞吞噬能力、肠粘膜屏障功能及血脑屏障功能均明显下降,体内有IETM的发生。
3、LPS可以通过p38、JNK、NF-κB信号转导通路激活BV-2细胞,释放炎症因子;促进BV-2细胞凋亡;使BV-2细胞钙稳态失衡,发生钙超载。从而从多个角度导致AD的发病。
综上所述,IETM是AD发生发展的重要影响因子之一。
Alzheimer's disease is the most prevalent form of dementia affecting more than 20 million people worldwide.AD was originally recognised by AloisAlzheimer in 1907 as a separate form of dementia.Furthermore,as a consequence of the worlds aging population,the prevalence of AD is expected to increase.This highlights the importance of research investigating the mechanisms behind the development of the disease.Apart from the recognisable behavioural differences,it is difficult to positively diagnose someone with Alzheimer's during the early stages of the disease.However the AD brain shows a consistent pathology amongst patients, with amyloid aggregates and neurofibrillary tangles evident in the AD brain.Intense research has identified genes involved in the development of these pathologies,namely the amyloid precursor protein and the presenilins.The increasing knowledge on AD pathogenesis has revealed the complex nature of this disease and highlights the need to elucidate the molecular mechanisms involved.This review discusses the current knowledge of the molecular mechanisms of Alzheimer Disease,focusing on amyloidogenesis,the role of the presenilin genes and the importance of animal models to further elucidate the mechanisms behind the development of the disease.The most common form of AD in the population(approximately 90%) occurs sporadically and is late in onset,usually occurring after 65 years of age.Familial Alzheimer's disease(FAD),only accounts for approximately 10%of cases and symptoms usually occur before the age of 65.The mode of inheritance of AD differs for each type.The majority of FAD and sporadic AD cases have a complex inheritance,while only 10%of FAD cases are inherited in an autosomal dominant pattern.In affected individuals the disease causes a progressive and permanent decline in memory and cognitive abilities.The first cognitive area affected is episodic memory.During disease progression,attention,executive functions,semantic memory,language and spatial orientation all begin to deteriorate.However the molecular,cellular and pathological triggers for the onset of the cognitive deterioration are poorly understood.
Since this original observation the two main histological features of amyloid plaques and neurofibrillary tangles(NFT) have been described in the AD brain.These features are found to be present in the temporal neocortex and hippocampal regions of the AD brain.The hippocampus resides in the cerebral cortex of the forebrain and is thought to be involved in memory storage.Amyloid plaques and NFTs result from an aberration in deposition of the amyloid beta peptide(Aβpeptide) and the hyperphosphorylated tau protein respectively and these depositions lead to neuronal loss and neurotoxicity in the AD affected brain.Accumulation of Aβpeptides may be the key event in pathogenesis of AD.The exact mechanism by which Aβpeptide deposition induces neurotoxicity is unclear,but it appears the oxidative stress plays an important role.Oxidative stress is extensive in AD and Aβpeptides stimulate oxidative stress by both direct and indirect mechanisms.Aβpeptides by themselves may act as enzymes,as they are capable of directly producing hydrogen peroxide and generating free radicals through metal ion reduction.As well,Aβpeptide can bind to mitochondrial proteins resulting in the generation of free radicals.Furthermore,Aβpeptides generate oxidative stress via neuroinflammation. Considerable evidence has supported that neuroinflammation is associated with AD pathology. The death of neurons observed in AD is partly attributed to the activation of two major brain cell types,astrocytes and microglia that participate in the immune/inflammatory response to Aβdeposition.However,these cells can have both neuroprotective and neurodegenerative functions.
Intestinal endotoxemia(IETM) was establish by Dewu Han in 1995,it claims that liver injury induced by various pathogenic factors(such as hepatitis virus,ethanol,drugs and hepatotoxicants,etc.) through their respective special pathogenesis is referred to as "primary liver injury"(PLI).Liver injury resulted from endotoxin(lipopolysaccharide,LPS) and the activation of Kupffer cells by LPS while intestinal endotoxemia(IETM) occurred during the occurrence and development of hepatitis is named the "secondary liver injury"(SLI).The after which has lost their own specificities of primary pathogenic factors is ascribed to IETM.The "secondary liver injury" is of important action and impact on development and prognosis of hepatitis.More severe IETM commonly results in excessive inflammatory responses,with serious hepatic necrosis,further severe hepatitis and even induces acute liver failure.Recent research show that IETM can be found in shock,stress,pancreatitis,and so on.
In IETM,LPS plays a important role,it can lead inflammatory reaction.All inflammatory reactions are also immune reactions.It is the innate immune system that is first called into action. Later,the adaptive system may also respond.Chronic inflammation signifies that an immune reaction is being sustained.That is because healing has failed to take place.Chronic inflammation may involve the innate immune system,the adaptive immune system,or a combination of the two.
AD is the prototypical autotoxic disorder.Classical immunologists had originally declared that it was a sterile,noninflammatory degenerative condition.The conclusion was based on the absence of infiltrating lymphocytes and monocytes which were easily observed in CNS infections and in presumed autoimmune diseases such as multiple sclerosis.This observation vindicated Hortega's original conclusion in 1919 that microglia were phagocytic cells of mesodermal origin.Moreover,it established that chronic infammafion could exist in the absence of leukocyte infiltration.
Two subsequent steps showed that the inflammation was self-damaging.The first was immunohistochemical,in which dystrophic neurites being damaged by the membrane attack complex of complement could be observed in AD tissue.The second was epidemiological,in which those taking anti-inflammatory agents appeared to be spared from AD.If the inflammation observed immunohistochemically had been beneficial instead of harmful,taking anti-inflammatories should have increased the risk of AD,and if they were merely cleaning up debris,then they should have had no effect.These epidemiological findings,which have been replicated in more than 20 studies,clearly show that the inflammation is contributing to the disease pathology,and that long-term consumption of NSAIDs reduces the risk of AD from twoto five fold.
Any reservations that might still be held that microglia are the sentinels of the brain that respond to disease pathology should have been dispelled by the recent in vivo movies.When an abnormality was induced by laser damage to a capillary,the microglia immediately changed to an activated morphology.Within minutes,they began migrating to the lesion site where they sealed off the affected area and commenced phagocytosing the extravasated blood.
Microglias are the brain representatives of van Furth's monocyte phagocytic system.Their counterparts,such as Langerhan's cells of the skin,Kupfer cells of the liver,osteoclasts of bone, and macrophages in many organs,are tissue-based phagocytes which can be presumed to carry out similar functions to microglia throughout the body.While it is only speculation at this stage, it might be anticipated that all cells of the monocyte phagocytic system would respond to pathological challenges in a similar fashion to those observed of brain microglia.
Inflammatory cytokines are more powerful mediators and are therefore a better target. Enbrel and Remicade,which block TNF,have had great success in treating rheumatoid arthritis. They are globulins which do not cross the blood-brain barrier and are therefore not suitable for CNS diseases.Nevertheless,they illustrate the promise of small molecules which could reach the brain and block the actions of TNF.Presumably,blockers of IL-1 and IL-6 would also be effective.Blockers of complement activation,especially the membrane attack complex,are also attractive targets for future therapy.As well,blockers of intracellular pathways that promote DNA transcription of inflammatory mediators should be effective.There are numerous reviews that cover the toxic effects of inflammatory mediators and the spectrum of possible agents or pathways to block in order to reduce such effects.
In order to explore the releationship between IETM and AD,we carry out this research. Our research includes three parts:
1、Research of the AD rat model by intraperitoneal injection with D-Gal and AlCl_3.
Methods:We established AD rat model by subjected to 90 days of intraperitoneal injection with D-galactose(60mg·kg~(-1)·d~(-1)) and aluminum trichloride(25mg·kg~(-1)·d~(-1)) to establish the Alzheimer disease's model,the TP、POD、T-AOC、CHAT、ACHE、NOS、NO in rat brain were detectd by kits.The learning and memory ability of the rats were observed by Morris water maze. The level of apoptosis,Tau、Aβ1-40 and express of APP、PS1 and BACE of rat brain were explored by TUNEL,ELISA,Immunohistochemistry and RT-PCR.
Results:The ability of learning and memory is obviously decreased in the rats treated with D-Galactose and AlCl_3 compared with the normal rats,while the express of APP、PS1 and BACE mRNA is increased.And there is apoptosis,deposition of Aβ1-40 and Tau in AD rat model.
Conclusion:Intraperitoneal injection with D-Gal and AlCl_3 can make AD rat model.
2、Research about the role of IETM in AD.
Methods:We explored the level of LPS,TNF-α、IL-1β、IL-10、DAO、Gln and Glutaminase in plasma of rat,the functional status of KC by immunohistochemistry,the level of S-100βin plasma and ZO-1 in brain by ELISA and Western blot.
Results:The level of LPS、TNF-α、IL-1β、IL-10、DAO、Gln and S-100βin AD rat model is raise up besides Glutaminase and ZO-1.
Conclusion:The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.The level of IETM in AD model was step up.
3、The mechanism of IETM influenced AD by use LPS to induce BV-2.
Methods:BV-2 was cultured in DMEM with FCS、PCN and STM.Set group as:BV-2+Aβ: 30min、1h、3h、6h、12h、24h;BV-2+LPS:30min、1h、3h、6h、12h、24h.Observe the morphous in inverted microscope.Detect the phagocytosis of BV-2 with polystyrene and expression of OX-42 with immunofluorescence.The level of TNF-α、IL-1βin clear supernatant was detectd by ELISA,the expression of p38、JNK、NF-κB was detect by Western blot.Apoptosis was detectd by flow cytometry and[Ca~(2+)]I was detect by Confocal Laser Scanning Microscope.
Results:LPS and Aβ1-40 can induce BV-2,promote it phagocytosis、up-regulation the expression of OX-42 and secretion of TNF-α、IL-1β,apoptosis and[Ca~(2+)]i was increased.The expression of p-p38,p-JNK and NF-κB increased too.
Conclusion:LPS can activate BV-2 to release TNF-α、IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38、JNK、NF-κB,finally induce AD.
Conclusion
1、Intraperitoneal injection with D-Gal and AlCl_3 can eatablish AD rat model.
2、The level of IETM in AD model was step up.The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.
3、LPS can activate BV-2 to release TNF-α、IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38、JNK、NF-κB;LPS can induce BV-2 apoptosis and calcium overload.Through these channels LPS finally induce AD.
In conclusion,there is IETM in AD,which play a important role.
AD在65岁以上的老年人有11%、80岁以上有50%会出现病症。其主要特征为智力的损伤,包括学习记忆、语言、读写、行为,以及对周围环境的识别,最终可导致死亡。其病理改变为弥漫性脑萎缩,以颞叶前、中部及海马、顶叶及前额叶区的萎缩最明显,脑室扩大,脑回变窄、脑沟加宽、脑裂加大;显微镜下可见神经原纤维缠结(NFT),老年斑(SPs)和颗粒空泡变性比健康老年人明显增多。多年来对AD的病因做了大量的研究,但迄今为止,病因仍不明,确切的致病因素并未找到。因为病因极其复杂,有患者自身的生物学因素,也有多种环境与社会因素的影响。
在AD发病机制的众多假说中,炎症机制假说占有重要的地位,大量的研究证明在AD发生过程中脑内有大量的炎性因子,如白介素-1(IL-1)、肿瘤坏死因子(tumor necrosisfactor-α,TNF-α)、白介素-6(IL-6)、转化生长因子β(Transforming Growth factorβ,TGF-β)、环氧化酶-2(Cyclooxygenase-2,COX-2)、补体及急性期反应蛋白的分泌。这些炎性因子通过一系列的信号转导途径,如NF-κB、丝裂原激活蛋白激酶((mitogen-αctivated proteinkinase,MAPK)途径激活神经小胶质细胞(microglia,MG)和星形细胞(astrocyte,AC),使之释放更多的炎性因子,同时它们又共同参与了脑局部炎症过程,与淀粉样蛋白(βamyloid,Aβ)和Tau蛋白的沉积紧密相关,这些研究确定了局部炎症在AD的病理生理过程中发挥了重要作用,甚至有的作者将炎症同SP和NFT共同并列为AD的3大主要特征。
韩德五教授于1995年首次提出的肝功能衰竭发生机制的肠源性内毒素血症(Intestinalendotoxemia,IETM)假说认为肠源性内毒素激活枯否细胞所分泌的多种活性物质(如细胞因子、炎性介质、自由基等)可引起“继发性肝损伤”,是导致多种急慢性肝病演化为肝功能衰竭发生的重要机制之一。大量的实验及临床研究证明,不但肝脏疾患伴有IETM,烫伤、烧伤、创伤、出血性休克、急性胰腺炎等多种疾病也伴有IETM。
在IETM中发挥核心作用的内毒素是革兰氏阴性杆菌细胞壁外膜表层构成成份,是脂多糖(LPS)与蛋白的复合体,是体内巨噬细胞最敏感的激活剂。正常肠道中含有大量的细菌和内毒素,生理状态下由于肠粘膜屏障的保护作用,肠腔中存在的内毒素只有极少量进入外周循环,对机体维持一定的免疫力可能有意义;同时肝脏的枯否细胞也会吞噬清除血液中过多的内毒素,防止IETM的发生。但是,当机体受到严重创伤(包括手术)、烧伤、放化疗和长期传统的肠外营养时,肠粘膜有可能发生通透性增高;或枯否细胞吞噬活性严重下降,对血浆中内毒素清除能力下降时,就有可能导致细菌及内毒素移位,引起内源性感染,甚至多脏器功能衰竭(MOF)。
内毒素是到目前为止已知的诱导IL-1、TNF-α等最重要的因子,可以充分激活巨噬细胞,释放大量炎症因子,激活细胞因子级联反应:
1、枯否细胞活化后可生成和释放TNF-α、IL-1、IL-6、血小板激活因子(platelet-activatedfactor,PAF)、PGs等细胞因之的分泌,损伤肝细胞;枯否细胞活化后所释放的白三烯,特别是LT-B_4具有强烈的化学趋化作用,吸引并激活中性粒细胞,产生并释放自由基,使细胞膜和细胞器膜发生脂质过氧化而损伤细胞。
2、枯否细胞活化后生成和释放的活性氧中间产物(ROI)可引发脂质过氧化反应,损伤生物膜系统、核酸和蛋白质导致肝细胞死亡。
3、枯否细胞与肝窦内皮细胞是花生四烯酸特别是PGD_2、PGE_2及血栓素的重要来源,可经对应的受体作用于肝细胞,引起蛋白磷酸化及膜稳定性变化。
通过以上机制,IETM会导致全身炎症反应综合症(SIRS)、多器官功能不全(MOD),甚至多器官功能衰竭(MOF)。
综上所述,IETM会导致机体发生严重的SIRS,而局部炎症在AD的病理生理过程中发挥了重要作用。那么同样高发于老年人的IETM与AD二者之间有何联系?IETM会不会是AD发病的一个危险因素?IETM在AD发病过程中有何作用?目前尚未见到相关报道,为此,我们设计了本次课题研究研究计划。
本研究由以下三个部分组成:
第一部分D-半乳糖和三氯化铝建立的AD大鼠模型的研究
实验目的及背景
关于AD的发病机制目前有胆碱能学说、基因突变和多态性学说、自身免疫学说、能量代谢障碍学说等。目前,依据各种学说已建立了多种AD动物模型,但每种模型均有一定的局限性,不能全面模拟AD的病理特征。为了建立一种准确可靠的AD模型,我们进行了本次实验,以期为AD研究提供一种新的大鼠模型。
大量研究表明,铝元素具有剂量与作用时间依赖性的诱导动物脑内发生病理变化,具有明显的神经毒作用,可引起明显的学习及记忆减退。D-半乳糖能较好的模拟小鼠的衰老表现,使小鼠机体出现与自然衰老相似的代谢紊乱特征,还引起脑神经元的一系列退行性改变,但腹腔注射D-半乳糖和AlCl_3制备阿尔茨海默病大鼠模型的报道还未见到。
实验方法
1、AD模型制备:模型组腹腔注射D-半乳糖60mg·kg~(-1)·d~(-1)(生理盐水配制,60g/L,给药量0.2ml/200g)和AlCl_3 25mg·kg~(-1)·d~(-1)(双蒸水配制,25g/L,给药量0.2ml/200g),连续90天;空白对照组腹腔注射等量的生理盐水和等量的双蒸水。
2、Morris水迷宫行为学实验
2.1定位航行实验水池分为N、E、S、W 4个象限。实验前1d将大鼠放入水池(不含平台)自由游泳2 min熟悉水迷宫环境,试验历时5d,每天分上午(n-1),下午(n-2)两个时间段,每段分别训练4次。训练开始时将平台置于SW象限,每个时间段分别从池壁4个起始点将大鼠面向池壁放入水池,记录每次找到平台的时间(逃避潜伏期,escape latency)和游泳路径。如大鼠在120s内找不到平台,由实验者将其引上平台,潜伏期记为120s,并记录为1次寻找站台错误,每次间隔4min让大鼠休息,再行下次试验。
2.2空间探索实验在第5天下午第5次训练时拆除水下平台,然后任选一个入水点将大鼠面向池壁放入水中,测其120s内在各象限的游泳距离及占总距离的百分率和120 s内跨越各象限平台相应位置次数及占总次数的百分率,并记录大鼠120s内搜索平台的路线图。
3、大鼠脑组织总蛋白(TP)、组织过氧化物酶(POD)、总抗氧化能力(T-AOC)、胆碱乙酰转移酶(ChAT)、胆碱酯酶(ChE)、一氧化氮(NO)、一氧化氮合酶(NOS)测定:取各组大鼠脑组织,分析天平称湿重,按脑组织:生理盐水0.2g:1.8ml比例制成10%脑组织匀浆,3000r/min,离心15min,取上清液,冻存待测。TP、POD、T-AOC、ChAT、ChE、NOS、NO试剂盒由南京建成生物制品有限公司提供,严格按照操作说明进行操作。
4、大鼠脑组织Tau蛋白浓度检测:双抗体夹心式酶联免疫吸附法(ELISA)。
5、大鼠脑组织凋亡测定:TUNEL法与流式细胞仪检测。
6、大鼠脑组织电镜观察:大鼠脑组织切成1mm~3大小的组织块,经2%二甲砷酸钠缓冲戊二醛和1%锇酸双固定,丙酮脱水,包埋,制成超薄切片,在JEM 100CX型透射电镜下观察脑组织的改变。
7、大鼠脑组织Aβ1-40检测:免疫组织化学法。
8、大鼠脑组织APP、PS1和BACE mRNA检测:两步法半定量逆转录聚合酶链反应(RT-PCR)技术检测。
实验结果
本部分实验通过给大鼠腹腔注射D-半乳糖和AlCl_3,不但复制出大鼠整体衰老过程、学习记忆力减退、脑组织ChAT活性降低、ChE活性升高所致乙酰胆碱能系统活性降低,脑组织抗氧化能力降低及NO系统活性增高等AD特征性的变化。同时,AD大鼠脑组织内APP、PS1、BACE mRNA表达增强、出现Aβ沉积、Tau蛋白含量增高、脑细胞凋亡、老年斑等AD的特征性病理变化。
实验结论
腹腔注射D-半乳糖和AlCl_3可以成功制备阿尔茨海默病模型,为AD的研究提供了一种新的大鼠模型。
第二部分IETM在AD模型发病中相关机制研究
实验目的及背景
IETM假说是韩德五教授于1995年首次提出的肝功能衰竭发生的机制。在IETM中发挥核心作用的内毒素可以激活枯否细胞分泌多种活性物质(如细胞因子、炎性介质、自由基等),可引起“继发性肝损伤”,甚至会导致全身炎症反应综合症(SIRS)、多器官功能不全(MOD),甚至多器官功能衰竭(MOF)的发生。大量的实验及临床研究证明,在烫伤、烧伤、创伤、出血性休克、急性胰腺炎等多种疾病也有IETM的发生。Goto等的研究表明337名72岁的老年人中有21.5%的老年人血浆内毒素水平高于正常,可见即使在正常人,IETM水平也随着年龄增长在逐渐升高。
炎症机制假说在AD发病机制的众多假说中占有重要的地位,大量的研究证明在AD发生过程中脑内有大量的炎性因子,如TNF-α、IL-1、IL-6、TGF-β、COX-2、补体及急性期反应蛋白的分泌。这些炎性因子通过一系列的信号转道途径,如NF-KB、MAPK途径激活神经MG和AC,使之释放更多的炎性因子,同时它们又共同参与了脑局部炎症过程,与Aβ和Tau蛋白的沉积紧密相关,这些研究确定了局部炎症在AD的病理生理过程中发挥了重要作用。
在我们所制备的AD模型体内是否也出现了IETM?如果是,IETM与AD二者之间有无内在的联系?IETM是否参与了AD的发病过程?IETM会不会是AD发病的一个危险因素?目前尚未见相关报道,为此我们进行了第二部分实验。
实验方法
1、血浆LPS、TNF-α、IL-1β及IL-10测定:采用改良过氯酸法检测血浆LPS含量,鲎试剂盒由上海医学化验所提供;放射免疫分析法测定血浆中TNF-α、IL-1β及IL-10含量,试剂盒由解放军总医院东亚免疫研究所提供。
2、大鼠肝脏枯否细胞功能状态检测:免疫组织化学SABC染色法检测肝组织溶菌酶LYZ阳性细胞-KC的数量和形态。
3、二胺氧化酶(Diamine oxidase,DAO)、谷氨酰胺(Glutamine,Gln)及谷氨酰胺酶(Glutaminase)活性检测:DAO采用黎君友等分光光度计法,谷氨酰胺采用酚一次氯酸法检测,谷氨酰胺酶活性采用荧光法测定。
4、肠粘膜常规HE染色,光镜下观察粘膜结构变化。
5、大鼠血清S-100β测定:双抗体夹心式酶联免疫吸附法(ELISA),试剂盒购自上海森雄生物科技有限公司。
6、大鼠脑组织ZO-1蛋白检测:免疫印迹法(Western blot)。
实验结果
腹腔注射D-半乳糖和AlCl_3制备的AD模型大鼠血浆中LPS、TNF-α、IL-1β及IL-10含量均明显升高,与对照组比较有统计学差异(P＜0.01);肝组织KC数量减少,吞噬LPS功能减弱;肠粘膜及血脑屏障通透性均明显升高,屏障功能明显下降。
实验结论
腹腔注射D-半乳糖和AlCl_3制备的AD模型大鼠KC吞噬功能、肠粘膜屏障及血脑屏障功能均明显下降,血浆中LPS及TNF-α、IL-1β等炎症因子含量增高,AD大鼠体内出现了IETM。
第三部分LPS激活BV-2细胞及其分子机制的研究
研究目的及背景
脑内炎症在AD、帕金森病等慢性神经变性疾病发病机理上发挥着重要作用。作为脑内固有免疫细胞的MG在AD发病中的急性与慢性神经炎症过程中均担当了重要的角色。
MG被激活后产生释放大量的前体炎症因子,可以产生细胞毒性因子(蛋白水解酶、细胞因子、兴奋性氨基酸、毗啶、2,3-二羧酸、补体蛋白、活性氧媒介物、一氧化氮等),Seabrook等的实验证明脑内炎症和MG有着密切关系,LPS诱导MG激活产生炎性细胞因子TNF-α、IL-1、IL-6,其信号转导途径有PTK途径、磷酸脂酶A_2(PLA_2)途径,还与细胞内核转录因子NF-κB、CREB等的活化有关。
有研究表明,Aβ在AD发病中的毒性作用机制可能与其扰乱细胞内钙稳态、产生活性氧和自由基、增加兴奋性毒性等作用有关。
我们通过体外培养BV-2细胞来研究在IETM中发挥核心致病作用的LPS对MG的激活作用、MG激活后释放的炎症因子在AD发病中的作用及其具体机制,从而进一步揭示IETM在AD发病中的作用及其机制。
实验方法
1、BV-2细胞培养:BV-2细胞株购自中国医科院协和医科大学基础医学细胞中心。含体积分数为0.1的胎牛血清的DMEM高糖培养基加青霉素100u/ml、链霉素100u/ml,置37℃、体积分数为0.05的CO_2的培养箱内培养,每隔1d换1次培养液,三四天传代1次。每次实验前细胞在含有10g/L牛血清白蛋白的DMEM培养基中培养48h后使细胞处于同步化状态。
2、BV-2细胞分组:BV-2(阴性对照组);BV-2+Aβ:30min、1h、3h、6h、12h、24h组;BV-2+LPS:30min、1h、3h、6h、12h、24h组。分别加入含有LPS(100ng/ml)、Aβ(20μg/ml)的培养基,培养30min、1h、3h、6h、12h、24h后,进行以下实验项目,每个处理组每个时间点观察6片。
3、BV-2细胞形态学观察:取对数生长期BV-2细胞接种于6孔培养板中(密度为2×10~5/孔),每组设3个平行孔,倒置显微镜下观察BV-2细胞形态,拍照。
4、BV-2细胞吞噬功能定量测定:参考Hirose的方法进行,细胞培养皿(10~4个细胞/片/皿)中加入聚苯乙烯乳珠0.5×10~8个,培养30min、1h、3h、6h、12h、24h后,PBS洗三次,洗去未被吞噬聚苯乙烯乳珠,直接倒置显微镜下对细胞所吞噬聚苯乙烯乳珠进行计数,观察,照像。每皿任取5个视野,每个视野随机数20个BV-2进行计数,取细胞吞噬聚苯乙烯乳珠数的平均值代表该皿细胞的吞噬功能。
5、BV-2细胞OX-42检测:免疫荧光法。Aβ1-40与LPS分别作用30min、1h、3h、6h、12h、24h后终止细胞培养,PBS清洗3次,丙酮室温固定,3%过氧化氢-甲醇室温下10min,正常山羊封闭血清,室温下孵育20min,滴加一抗5μl(小鼠抗大鼠OX-421:100),湿盒内37℃孵育2h,二抗(FITC),室温1h,倒置显微镜观察拍照。每皿任取5个视野,取每个视野OX-42阳性表达细胞数及荧光强度代表该皿细胞的活性。
6、BV-2细胞培养上清液TNF-α、IL-1β测定:双抗体夹心式酶联免疫吸附法(ELISA)。
7、BV-2细胞凋亡检测:各组细胞用PBS制成细胞悬液,不低于1×10~6个细胞/管,20%冰乙醇固定,轻轻混匀,PBS洗1次,重悬于500μlPBS后流式细胞仪检测。
8、BV-2细胞p38、JNK、NF-κB蛋白表达水平检测:免疫印迹法(Western blot)。
9、BV-2细胞[Ca~(2+)]i变化检测:按实验要求培养的BV-2,加入终浓度为10μmol/L的Fluo-3/AM,37℃负载40min,置于MRC-1024型共聚焦显微镜下,488nm激发波长,522nm发射波长扫描。细胞游离[Ca~(2+)]i动态测定:选定待测BV-2细胞后,先预扫4min获得基线值,继续扫描至4min时分别各自快速加入LPS 100ng/ml和Aβ1-40 20μg/ml观察荧光值的变化,用随机附带的Time-course/Rationmetric软件给出加药前后神经元内荧光值随时间变化的曲线。每皿取5个视野,每个视野随机选取10个BV-2细胞进行荧光值统计。荧光值强度代表[Ca~(2+)]i的浓度。
实验结果
Aβ1-40与LPS均可以激活BV-2细胞,使其形态发生明显变化,吞噬能力增强,OX-42表达增强,TNF-α、IL-1β分泌增多,凋亡率较对照组明显升高(P＜0.01),p-p38、p-JNK及NF-κB表达水平均明显高于对照组,[Ca~(2+)]i明显升高。
实验结论
LPS可以通过p38、JNK、NF-κB信号转导通路迅速激活BV-2细胞,提高其吞噬能力,促进其分泌炎症因子;而且,LPS对BV-2细胞还有促凋亡作用,并可以使BV-2细胞钙稳态失衡,发生钙超载。
LPS对BV-2的这种激活作用与Aβ1-40相似,可见LPS在AD的发病中发挥了与Aβ1-40类似的致病作用。
通过以上三部分研究,我们可以得出以下结论:
1、腹腔注射D-半乳糖和AlCl_3可以成功制备AD大鼠模型。
2、AD模型大鼠血浆中LPS及炎症因子水平升高,枯否细胞吞噬能力、肠粘膜屏障功能及血脑屏障功能均明显下降,体内有IETM的发生。
3、LPS可以通过p38、JNK、NF-κB信号转导通路激活BV-2细胞,释放炎症因子;促进BV-2细胞凋亡;使BV-2细胞钙稳态失衡,发生钙超载。从而从多个角度导致AD的发病。
综上所述,IETM是AD发生发展的重要影响因子之一。
Alzheimer's disease is the most prevalent form of dementia affecting more than 20 million people worldwide.AD was originally recognised by AloisAlzheimer in 1907 as a separate form of dementia.Furthermore,as a consequence of the worlds aging population,the prevalence of AD is expected to increase.This highlights the importance of research investigating the mechanisms behind the development of the disease.Apart from the recognisable behavioural differences,it is difficult to positively diagnose someone with Alzheimer's during the early stages of the disease.However the AD brain shows a consistent pathology amongst patients, with amyloid aggregates and neurofibrillary tangles evident in the AD brain.Intense research has identified genes involved in the development of these pathologies,namely the amyloid precursor protein and the presenilins.The increasing knowledge on AD pathogenesis has revealed the complex nature of this disease and highlights the need to elucidate the molecular mechanisms involved.This review discusses the current knowledge of the molecular mechanisms of Alzheimer Disease,focusing on amyloidogenesis,the role of the presenilin genes and the importance of animal models to further elucidate the mechanisms behind the development of the disease.The most common form of AD in the population(approximately 90%) occurs sporadically and is late in onset,usually occurring after 65 years of age.Familial Alzheimer's disease(FAD),only accounts for approximately 10%of cases and symptoms usually occur before the age of 65.The mode of inheritance of AD differs for each type.The majority of FAD and sporadic AD cases have a complex inheritance,while only 10%of FAD cases are inherited in an autosomal dominant pattern.In affected individuals the disease causes a progressive and permanent decline in memory and cognitive abilities.The first cognitive area affected is episodic memory.During disease progression,attention,executive functions,semantic memory,language and spatial orientation all begin to deteriorate.However the molecular,cellular and pathological triggers for the onset of the cognitive deterioration are poorly understood.
Since this original observation the two main histological features of amyloid plaques and neurofibrillary tangles(NFT) have been described in the AD brain.These features are found to be present in the temporal neocortex and hippocampal regions of the AD brain.The hippocampus resides in the cerebral cortex of the forebrain and is thought to be involved in memory storage.Amyloid plaques and NFTs result from an aberration in deposition of the amyloid beta peptide(Aβpeptide) and the hyperphosphorylated tau protein respectively and these depositions lead to neuronal loss and neurotoxicity in the AD affected brain.Accumulation of Aβpeptides may be the key event in pathogenesis of AD.The exact mechanism by which Aβpeptide deposition induces neurotoxicity is unclear,but it appears the oxidative stress plays an important role.Oxidative stress is extensive in AD and Aβpeptides stimulate oxidative stress by both direct and indirect mechanisms.Aβpeptides by themselves may act as enzymes,as they are capable of directly producing hydrogen peroxide and generating free radicals through metal ion reduction.As well,Aβpeptide can bind to mitochondrial proteins resulting in the generation of free radicals.Furthermore,Aβpeptides generate oxidative stress via neuroinflammation. Considerable evidence has supported that neuroinflammation is associated with AD pathology. The death of neurons observed in AD is partly attributed to the activation of two major brain cell types,astrocytes and microglia that participate in the immune/inflammatory response to Aβdeposition.However,these cells can have both neuroprotective and neurodegenerative functions.
Intestinal endotoxemia(IETM) was establish by Dewu Han in 1995,it claims that liver injury induced by various pathogenic factors(such as hepatitis virus,ethanol,drugs and hepatotoxicants,etc.) through their respective special pathogenesis is referred to as "primary liver injury"(PLI).Liver injury resulted from endotoxin(lipopolysaccharide,LPS) and the activation of Kupffer cells by LPS while intestinal endotoxemia(IETM) occurred during the occurrence and development of hepatitis is named the "secondary liver injury"(SLI).The after which has lost their own specificities of primary pathogenic factors is ascribed to IETM.The "secondary liver injury" is of important action and impact on development and prognosis of hepatitis.More severe IETM commonly results in excessive inflammatory responses,with serious hepatic necrosis,further severe hepatitis and even induces acute liver failure.Recent research show that IETM can be found in shock,stress,pancreatitis,and so on.
In IETM,LPS plays a important role,it can lead inflammatory reaction.All inflammatory reactions are also immune reactions.It is the innate immune system that is first called into action. Later,the adaptive system may also respond.Chronic inflammation signifies that an immune reaction is being sustained.That is because healing has failed to take place.Chronic inflammation may involve the innate immune system,the adaptive immune system,or a combination of the two.
AD is the prototypical autotoxic disorder.Classical immunologists had originally declared that it was a sterile,noninflammatory degenerative condition.The conclusion was based on the absence of infiltrating lymphocytes and monocytes which were easily observed in CNS infections and in presumed autoimmune diseases such as multiple sclerosis.This observation vindicated Hortega's original conclusion in 1919 that microglia were phagocytic cells of mesodermal origin.Moreover,it established that chronic infammafion could exist in the absence of leukocyte infiltration.
Two subsequent steps showed that the inflammation was self-damaging.The first was immunohistochemical,in which dystrophic neurites being damaged by the membrane attack complex of complement could be observed in AD tissue.The second was epidemiological,in which those taking anti-inflammatory agents appeared to be spared from AD.If the inflammation observed immunohistochemically had been beneficial instead of harmful,taking anti-inflammatories should have increased the risk of AD,and if they were merely cleaning up debris,then they should have had no effect.These epidemiological findings,which have been replicated in more than 20 studies,clearly show that the inflammation is contributing to the disease pathology,and that long-term consumption of NSAIDs reduces the risk of AD from twoto five fold.
Any reservations that might still be held that microglia are the sentinels of the brain that respond to disease pathology should have been dispelled by the recent in vivo movies.When an abnormality was induced by laser damage to a capillary,the microglia immediately changed to an activated morphology.Within minutes,they began migrating to the lesion site where they sealed off the affected area and commenced phagocytosing the extravasated blood.
Microglias are the brain representatives of van Furth's monocyte phagocytic system.Their counterparts,such as Langerhan's cells of the skin,Kupfer cells of the liver,osteoclasts of bone, and macrophages in many organs,are tissue-based phagocytes which can be presumed to carry out similar functions to microglia throughout the body.While it is only speculation at this stage, it might be anticipated that all cells of the monocyte phagocytic system would respond to pathological challenges in a similar fashion to those observed of brain microglia.
Inflammatory cytokines are more powerful mediators and are therefore a better target. Enbrel and Remicade,which block TNF,have had great success in treating rheumatoid arthritis. They are globulins which do not cross the blood-brain barrier and are therefore not suitable for CNS diseases.Nevertheless,they illustrate the promise of small molecules which could reach the brain and block the actions of TNF.Presumably,blockers of IL-1 and IL-6 would also be effective.Blockers of complement activation,especially the membrane attack complex,are also attractive targets for future therapy.As well,blockers of intracellular pathways that promote DNA transcription of inflammatory mediators should be effective.There are numerous reviews that cover the toxic effects of inflammatory mediators and the spectrum of possible agents or pathways to block in order to reduce such effects.
In order to explore the releationship between IETM and AD,we carry out this research. Our research includes three parts:
1、Research of the AD rat model by intraperitoneal injection with D-Gal and AlCl_3.
Methods:We established AD rat model by subjected to 90 days of intraperitoneal injection with D-galactose(60mg·kg~(-1)·d~(-1)) and aluminum trichloride(25mg·kg~(-1)·d~(-1)) to establish the Alzheimer disease's model,the TP、POD、T-AOC、CHAT、ACHE、NOS、NO in rat brain were detectd by kits.The learning and memory ability of the rats were observed by Morris water maze. The level of apoptosis,Tau、Aβ1-40 and express of APP、PS1 and BACE of rat brain were explored by TUNEL,ELISA,Immunohistochemistry and RT-PCR.
Results:The ability of learning and memory is obviously decreased in the rats treated with D-Galactose and AlCl_3 compared with the normal rats,while the express of APP、PS1 and BACE mRNA is increased.And there is apoptosis,deposition of Aβ1-40 and Tau in AD rat model.
Conclusion:Intraperitoneal injection with D-Gal and AlCl_3 can make AD rat model.
2、Research about the role of IETM in AD.
Methods:We explored the level of LPS,TNF-α、IL-1β、IL-10、DAO、Gln and Glutaminase in plasma of rat,the functional status of KC by immunohistochemistry,the level of S-100βin plasma and ZO-1 in brain by ELISA and Western blot.
Results:The level of LPS、TNF-α、IL-1β、IL-10、DAO、Gln and S-100βin AD rat model is raise up besides Glutaminase and ZO-1.
Conclusion:The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.The level of IETM in AD model was step up.
3、The mechanism of IETM influenced AD by use LPS to induce BV-2.
Methods:BV-2 was cultured in DMEM with FCS、PCN and STM.Set group as:BV-2+Aβ: 30min、1h、3h、6h、12h、24h;BV-2+LPS:30min、1h、3h、6h、12h、24h.Observe the morphous in inverted microscope.Detect the phagocytosis of BV-2 with polystyrene and expression of OX-42 with immunofluorescence.The level of TNF-α、IL-1βin clear supernatant was detectd by ELISA,the expression of p38、JNK、NF-κB was detect by Western blot.Apoptosis was detectd by flow cytometry and[Ca~(2+)]I was detect by Confocal Laser Scanning Microscope.
Results:LPS and Aβ1-40 can induce BV-2,promote it phagocytosis、up-regulation the expression of OX-42 and secretion of TNF-α、IL-1β,apoptosis and[Ca~(2+)]i was increased.The expression of p-p38,p-JNK and NF-κB increased too.
Conclusion:LPS can activate BV-2 to release TNF-α、IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38、JNK、NF-κB,finally induce AD.
Conclusion
1、Intraperitoneal injection with D-Gal and AlCl_3 can eatablish AD rat model.
2、The level of IETM in AD model was step up.The intestinal mucosa barrier and BBB were damaged,phagocytosis of KC was decreased.
3、LPS can activate BV-2 to release TNF-α、IL-1β.Latter lead to Inflammatory reaction through signal transduction,such as p38、JNK、NF-κB;LPS can induce BV-2 apoptosis and calcium overload.Through these channels LPS finally induce AD.
In conclusion,there is IETM in AD,which play a important role.
引文
[1]韩德五,肝功能衰竭发病机制的研究-肠源性内毒素血症假说[J].中华肝脏病杂志,1995,3(3):134-7.
[2]Han DW.Intestinal endotoxemia as a pathogenetic mechanism in liver failure(Topic Comment)[J].World J Gaotroenteral,2002,8(6):961-5.
[3]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[4]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细胞化学研究[J].西安医科大学学报(中文版),1997,18(3):304-7.
[5]White DM,Longstreth WT Jr,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[6]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) in mice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[7]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration ofdeferoxamine[J].Behav Neurosci,1989,103:779.
[8]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[9]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-5.
[10]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-8.
[11]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[12]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-2.
[13]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(中国药理学报),2001,22(12):1078-83.
[14]Goto T,Eden S,Nordenstam G,et al.Endotoxin levels in sera of elderly individuals[J].Clin Diagn Lab Immunol,1994,1(6):684-8.
[15]黎君友,于燕,郝军,等.分光光发法测定血和小肠组织二胺氧化酶活性[J].氨基酸和生物资源,1996,18(4):28-30.
[16]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[17]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[18]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].Prog BrainRes,2001,132:555-65.
[19]Pocock JM,Liddle AC,Hooper C,etal.Activated microglia in Alzheimer' s disease and stroke[J].Ernst Schering Res Found Workshop,2002(39):105-32.
[20]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[21]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[22]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell iniury via anitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[23]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson' s disease[J].Biochim Biophys Acta,1997,1362:77-86.
[24]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[25]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation- mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[26]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[27]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation andhuman microglial activation[J].Glia,2006,53:233-40.
[28]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[29]Hanasaki K,Yokota Y,Ishizaki J.et al.Resistance to endotoxic shock in phospholipase A2 reeeptor defieient mice[J].J Biol Chem,1997,272:32792-7.
[30]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extraeellular ATP[J].J Immunol,1996,156:1531-9.
[31]Kaltschmidt CB,Lallnes Vieiva J,Kreutzberg Gw,et al.Transcription factor NF-κB is activated in microglial during experimental autoimmune encephalomyelitis [J].J Neuro Immunol,1994,55:99-106.
[32]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia [J].J Neuroimmunol,1998,92(1-2):170-8.
[33]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cel lines:expression of cytokines and chemokines [J].Neurobiol Dis,2001,8(6):1057-68.
[34]Kawahara M,Kuroda Y.Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein:channel formation and disruption of calcium homeostasis [J].Brain Res Bull,2000,53(4):389-97.
[35]Suh YH.An etiological role of amyloidogenic carboxy-terminat fragments of the beta-amyloid precursor protein in Alzheimer's disease [J].J Neurochem,1997,68;1781-91.
[36]Weiss JH,Pike CJ,Cotman CW,et al.Ca channel blockers attenuate amyloid peptides toxicity to cortical neurons in culture [J].J Neurochem,1994,62:372-375.
[37]Ingram VM.The role of Alzheimer A beta peptides in ion transport across cell membranes [J].Subcell Biochem,2005,38:339-49.
[38]Ca C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chroinc application of beta-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203:61-65.
[39]Guo Q,Robinson N,Mattson M.Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant prusenilin-1 by activation of NF-kappa B and stabilization of calcium homeostasis [J].J Biol Chem,1998,273:12341-51.
[1]Small GW,Rabins PV,Barry PP,et al.Diagnosis and treatment of Alzheimer disease and related disorders.Consensus statement of the American Association for Geriatric Psychiatry,the Alzheimer's Association,and the American Geriatrics Society[J].JAMA,1997,278(16):1363-71.
[2]Labo LJ,Launer LJ,Fratiglioni L,et al.Prevalence of dementia and major subtypes in Europe:A collaborative study of population basedcohorts[J].Neurology,2000,54(suppl5):s4-s9.
[3]邹开利,漆静,何源,等.重庆渝中区街道老年期痴呆横断面研究[J].中华老年医学杂志,2002,21(6):433-6.
[4]屈秋民,乔晋,扬剑波,等.西安地区中老年人的痴呆患病率调查[J].中华老年医学杂志,2001,20(4):283-6.
[5]张振馨,魏镜,洪霞,等.北京城乡痴呆及其主要亚型的患病率[J].中华神经科杂志,2001,34(5):199-203.
[6]周玢,洪震,黄茂盛.上海城市人群痴呆患病率调查[J].中华流行病学杂志,2001, 22(5):368-72.
[7]唐牟尼,刘协和,邹晓毅,等.成都地区老年期痴呆患病率调查[J].中华精神科杂志,2001,34(4):226-30.
[8]余金龙,冯容妹,方小心,等.广东省沿海地区农村老年期痴呆的患病率调查[J].中国神经精神杂志,1998,24(1):30-2.
[9]Kchin HFK,Lain LCW,Chi I,et al.Prevelence of dementia in Chinese elderly in Hong Kong[J].Neurology,1998,50:1002-9.
[10]吕书臣,余海民,陈勇华,等.舟山市定海城区老年痴呆流行病学调查[J].中华精神科杂志,1998,31(4):225-7.
[11]高至胜,盛小奇,单飞豹,等.湖南省长沙市老年期痴呆流行病学调查[J].湖南医学,1994,11(4):195-6.
[12]唐牟尼,郭杨波,向孟泽,等.农村老年期痴呆和Alzheimer病流行病学调查报告[J].临床精神医学杂志,1999,9(1):20-2.
[13]王天祥,孙建中,韦学斌,等.安徽某地区、农村老年性痴呆流行病学调查[J].职业与健康,1999,15(11):43-5.
[14]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neual,1999,56(9):1121-3.
[15]胡昔权,钱采韵,窦祖林,等.Alzheimer病与老年脑中β淀粉样蛋白免疫组化的研究[J].中国神经精神疾病杂志,1998,24(1):6.
[16]Mcquade R,Young A H.Future therapeutic targets in mood disorders:the glucocorticoid receptor[J].Br J Psychiatry,2000,177(2):390-5.
[17]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[18]李权益,高薮幔.分子医学--艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-180.
[19]Weller R O,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:110-7.
[20]陈明,李爱媛.Alzheimer病与神经元钙稳态[J].生命的化学,1997,17(3):46-9.
[21]Rogers J,Webster S,Lue LF,et al.Inflammation and Alzheimer's disease pathogenesis [J].NeurobiolAging,1996,17(5):681-6.
[22]Blasko I,Veerhuis R,Stampfer-Kountchev M,et al.Costimulatory effects of interferongamma and interleukin-1 beta or rumor necrosis factor alpha on the synthesis of A betal-40 and A betal-42 by human asteocytes[J].Neurobiol Dis,2000,7(6 Pt B):682-9.
[23]Lukiw WJ,Bazan NG.Neuroinflammatory signaling upregulation in Alzheimer's disease[J].Neurochem Res,2000,25(9210):1173-84;
[24]Mattson MP.Apoptosis in neurodegenerative disorders[J].Nat Pev Mol Cell Biol,2000,1(2):120-9.
[25]Tan J,Town T,Mori T,et al.CD45 opposes beta amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase[J].Neurosci,2000,20(20):7587-94.
[26]Combs CK,Karlo JC,Kao SC,et al.beta Amyloid stimulation of microglia and monocytes results in TNF alpha-dependant expression of inducible nitric oxide synthase and neuronal apoptosis[J].Neurosci,2001,21(4):1179-88.
[27]Brahimi F,Bertrand P,Starck M,et al.Control of apolipoprotein E secretion in the human hepatoma cell line KYN22[J].Cell Biochem Funct,2001,19(1):51-8.
[28]Gitter BD,Boggs LN,May PC,et al.Regulation of cytokine secretion and amyloid precursor protein processing by proinflammatory amyloid Peta(A beta)[J].Ann N Y AcADSci,2000,917:154-64.
[29]Cagnin A,Brooks DJ,Kennedy AM,et al.Invivo measurement of activated microglia in dementia[J].Lancet,2001,358(9280):461-7.
[30]Dandrea MR,Reiser PA,Gumula NA,et al.Application of triple immuno-histochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer's disease[J].Biotech Histochem,2001,76(2):97-106.
[31]Giulian D,Haverkamp LJ,Yu JH,et al.Specific domains of beta-amyloid from Alzheimer's plaque elicit neuron killing in human microglia[J].J Neurosci,1996,16(19):6021-37
[32]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo[J].Exp Neurol,2000,163(2):388-91.
[33]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation[J].Neurochem Int,2001,39(526):341-8.
[34]Grammas P,Ovase R.Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain[J].Am J Pathol,2002,160(5):1583-7.
[35]Hoozemans J,Veerhuis R,Janssen I,et al.The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia:implications for Alzheimer's disease[J].Brain Res,2002,951(2):218-26.
[36]O'Banion MK,Miller JC,Chang JW,et al.Interleukin-1 beta induces prostaglandin G/H synthase-2(cyclooxygenase-2) in primary murineastrocyte cultures[J].J Neuro chem,1996,66(6):2532-40.
[37]Ho L,Pieroni C,Winger D,et al.Regionaldistribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease[J].J Neurosci Res,1999,57(3):295-303.
[38]Xiang Z,Ho L,Yemul S,et al.Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology[J].Gene Expr,2002,10(526):271-8.
[39]Webster SD,Yang AJ,Margol L,et al.Complement component C1q modulates the phagocytosis of A beta by microglia[J].Exp Neurol,2000,161(1):127-38.
[40]Shen Y,Lue L,Yang L,et al.Complement activation by neurofibrillary tangles in Alzheimer's disease[J].Neurosci Lett,2001,305(3):165-8.
[41]Bradt BM,Kolb WP,Cooper NR.Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide[J].J Exp Med,1998,188(3):431-8.
[42]McGeer EG,Yasojima K,Schwab C,et al.The pentraxins possible role in Alzheimer's disease and other innate inflammatory disease[J].Neurobiol Aging,2001,22(6):843-8.
[43]McGeer PL,Walker DG,Pitas RE,et al.Apolipoprotein E4(ApoE4) but not ApoE3 or ApoE2 potentiates beta-amyloid protein activation of complement in vitro[J].Brain Res,1997,749(1):135-8.
[44]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:110-7.
[45]韩德五,肝功能衰竭发病机制的研究-肠源性内毒素血症假说[J].中华肝脏病杂志,1995,3(3):134-7
[46]Han DW.Intestinal endotoxemia as a pathogenetic mechanism in liver failure(Topic Comment)[J].World J Gaotroenteral,2002,8(6):961-5.
[47]Goto T,Eden S,Nordenstam G,et al.Endotoxin levels in sera of elderly individuals[J].Clin Diagn Lab Immunol,1994,1(6):684-8.
[48]Wilmore DW,Smith RJ,O'Dwyer ST,et al.The gut:A central organ after surgical stress[J].Sugery,1988,104:917-23.
[49]Marshall J,Sweeney D.Microbial Infection and the septic response in critical surgical [J].Arch Surg,1990,125:17-23.
[50]徐鹏远,蒋朱明,孙永华,等.手术/创伤后外周血内毒素研究[J].中华实验外科,1999,16:298-9.
[51]Faries PL,Simon RJ,Martella AT,et al.Intestinal permeability correlates with severity of injury in trauma patients[J].J Trauma,1998,44:1031-6.
[52]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[53]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细 胞化学研究.西安医科大学学报(中文版),1997,18(3):304-7.
[54]White DM,Longstreth WT Jr,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[55]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) inmice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[56]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration of deferoxamine[J].Behav Neurosci,1989,103:779.
[57]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[58]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-5.
[59]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-8.
[60]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[61]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-2.
[62]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(中国药理学报),2001,22(12):1078-83.
[63]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[64]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[65]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].Prog Brain Res,2001,132:555-65.
[66]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke[J].Ernst Schering Res Found Workshop,2002(39):105-32.
[67]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[68]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[69]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[70]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation and human microglial activation[J].Glia,2006,53:233-40.
[71]Chao CC,Hu S,MolitorTW,et al.Activated microglia mediate neuronal cell iniury via a nitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[72]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease[J].Biochim Biophys Acta,1997,1362:77-86.
[73]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[74]Liu B,Gao HM,W ang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[75]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[76]Hanasaki K,Yokota Y,Ishizaki J,et al.Resistance to endotoxic shock in phospholipase A2 receptor deficient mice[J].J Biol Chem,1997,272:32792-7.
[77]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extracellular ATP[J].J Immunol,1996,156:1531-9.
[78]Kaltschmidt CB,Lallnes Vieiva J,Kreutzberg Gw,et al.Transcription factor NF KB is activated in microglial during experimental autoimmune encephalomyelitis[J].J Neuro Immunol,1994,55:99-106.
[79]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia[J].J Neuroimmunol,1998,92(1-2):170-8.
[80]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cel lines:expression of cytokines and chemokines[J].Neurobiol Dis,2001,8(6):1057-68.
[1]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004:18(1):22-26.
[2]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[3]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细胞化学研究[J].西安医科大学学报(中文版),1997,18(3):304-7.
[4]White DM,Longstreth WT JR,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[5]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) inmice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[6]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration of deferoxamine[J].Behav Neurosci,1989,103:779.
[7]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[8]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-95.
[9]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-58.
[10]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[11]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-62.
[12]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(可路药理学报),2001,22(12):1078-83.
[1]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann NY Acad Sci,2000,903:110-7.
[2]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[3]李权益,高薮幔.分子医学--艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-180.
[4]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neural,1999,56(9):1121-3.
[5]吴江,张昱.无名质区破坏的wistar大鼠脑内胆碱乙酰转移酶和生长抑素活性的变化及相互关系[J].中风与神经疾病杂志,1995,3:911.
[6]Salvaterra PM.Molecular biology and neurobiology of choline acetyltransferase[J].Mol Neurobiol,1987,1(3):247.
[7]Markesbery WR.Oxidative stress hypothesis in Alzheimer's disease[J].Free Radic Biol Med,1997,23(1):134-47.
[8]O'Mahony S,Harkany T,Rensink AA,et al.Beta amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex:reversal by NMDA receptor blockade[J].BrainRes,1998,45(4):405-11.
[9]Wevers A,Monteggia L,Nowacki S,et al.Expression of nicotinic acetyl choline receptor subunits in the cerebralcortex in Alzheimer's disease:histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein[J].J Eur Neurosci,1999,11(7):2551-65.
[10]Law A,Gauthier S,Quirion R.Say NO to Alzheimer's disease:the putative links between nitric oxide,and dementia of the Alzheimer's type[J].Brain Res Rev,2001,35:73-96.
[11]Meyer RC,Spangler EL,Kametani H,et al.Ageassociated memory impairment:Assessing the role of nitric oxide[J].Ann NY Acad Sci,1998,854:307-17.
[12]Pluta R,Misicka A,Nidan RU,et al.Transport of human beta-amyloid peptide through the rat blood brain barrier after global cerebral is chemia[J].Acta Neurochir,1997,70(suppl):247-9.
[1]Hockenbery D.Defining apoptosis[J].Am J Pathol,1995,146(1):16-9.
[2]Lassmann H,Bancher C,Breitschopf H,et al.Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ[J].Acta Neuropathol,1995,89(1):35-41.
[3]Su JH,Anderson AJ,Cummings BJ,et al.Immunohistochemical evidence for apoptosis in Alzheimer's disease[J].Neuroreport,1994,5:2529-33.
[1]Glenner G G,Wong C W.Alzheimer's disease:initial report of the purification and characterization of a novel cerebro vascular amyloid protein[J].Biochem Biophys Res Commun,1984,120(3):885-90.
[2]Hardy J A,Higgins G A.Alzheimer's disease:the amyloidcascade hypothesis[J].Science,1992,256(5054):184-5.
[3]Yankner B A,Dawes L R,Fisher S,et al.Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease[J].Science,1989,245(4916):417-20.
[4]Frautschy S A,Baird A,Cole G M.Effects of injected Alzheimer β-amyloid cores in rat brain[J].Proc Natl AcADSci USA,1991,88(19):8362-6.
[5]Pike C J,Walencewicz A J,Glabe C G,et al.In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity[J].Brain Res,1991,563(1-2):311-4.
[6]Lesne S,Koh M T,Kotilinek L,et al.A specific amyloid-b protein assembly in the brain impairs memory[J].Nature,2006,440(7082):352-7.
[7]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid p protein deposition[J].ActaNeuropathol(Bed),1997,94:316-22.
[8]Koo EH,Park L,Selkoe DJ.Amyloid P-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth[J].Proc Natl AcADSci USA,1993,90:4748-52.
[9]Behl C.Amyloid P-protein toxicity and oxidative stress in Alzheimer's disease[J].Cell Tissue Res,1997,290:471-80.
[10]Cotter RL,Burke WJ,Thomas VS,et al.Insights into the neurodegenerative process of Alzheimer's disease:a role for mononuclear phagocyte-associated inflammation and neurotoxicity[J].J Leukoc Biol,1999,65:416-27.
[11]Casal C,Serratosa J,Tusell JM.Effects of P-AP peptides on activation of the transcription factor NF-κB and in cell proliferation in glial cell cultures[J].Neurosci Res,2004,48:315-23.
[12]E1 Khoury J,Hickman SE,Thomas CA,et al.Scavenger receptor-mediated adhesion ofmicmglia to β-amyloid fibrils[J].Nature,1996,382:716-9.
[13]Roy A,Fung YK,Liu X,et al.Up-regulacion of microglial CD 11b expression by nitric oxide[J].J Biol Chem,2006,281:14971-80.
[14]Lorton D.β-Amyloid-induced IL-1β release from an activated human monocyte cell line is calcium-and G-protein-dependent[J].Mech Ageing Dev,1997,94:199-211.
[15]Combs CK,Johnson DE,Cannady SB,et al.Identifcation of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of β-amyloid and prion proteins[J].J Neurosci,1999,19:928-39.
[16]Verdier Y,Zarandi M,Penke B.Amyloid b-peptide interactions with neuronal and glial cell plasma membrane:binding sites and implications for Alzheimer's disease[J].J Pept Sci,2004,10(5):229-48.
[17]Kim H S,Lee J H,Lee J P,et al.Amyloid b peptide induces cytochrome C release from isolated mitochondria[J].Neuroreport,2002,13(15):1989-93.
[18]Probst A,Langui D,Ulrich J.Alzheimer's disease:a description of the structural lesions[J].BrainPathol,1991,1(4):229-239.
[19]Meda L,Bernasconi S,Bonaiuto C,et al.P-amyloid(25-35) peptide and IFN-g synergistically induce the production of the chemotactic cytokine MCP-l/JE in monocytes and microglial cells[J].J Immunol,1996,157(3):1213-8.
[20]Mark R J,Hensley K,Butterfield DA,et al.Amyloid b-peptide impairs ionmotive ATPase activities:evidence for a role in loss of neuronal Ca~(2+) homeostasis and cell death[J].J Neurosci,1995,15(9):6239-49.
[21]Davidson RM,Shajenko L,Donta TS.Amyloid P-peptide(AP P) potentiates a nimodipine-sensitive L-type barium conductance in NlE-115 neuroblastoma cells[J].Brain Res,1994,643(1-2):324-7.
[22]Mattson MP,Cheng B,Davis D,et al.P-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity[J].J Neurosci,1992,12(2):376-89.
[23]Behl C,Davis J B,Lesley R,et al.Hydrogen peroxide mediates amyloid β protein toxicity[J].Cell,1994,77(6):817-27.
[24]Butterfield D A,Hensley K,Harris M,et al.b-Amyloid peptide free radical fragments initiate synaptosomal Hpoperoxidation in a sequence-specificfashion:implications to Alzheimer's disease[J].Biochem Biophys Res Commun,1994,200(2):710-5.
[25]Cafe C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chronic application of β-amyloid fragment 25-35 in cortical cultures[J].Neurosci Lett,1996,203(1):61-5.
[26]Mattson M P.Pathways towards and away from Alzheimer's disease[J].Nature,2004,430(7000):631-9.
[27]Casley CS,Land JM,Sharpe MA,et al.P-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons[J].Neurobiol Dis,2002,10(3):258-67.
[28]Blass J P.Brain metabolism and brain disease:is metabolic deficiency the proximatecause of Alzheimer dementia?[J].J Neurosci Res,2001,66(5):851-6.
[29]Takashima A,Honda T,YasutakeK,et al.Activation of tau protein kinase I/glycogen synthase kinase-3b by amyloid βeta peptide(25-35) enhances phosphorylation of tau in hippocampal neurons[J].Neurosci Res,1998,31(4):317-23.
[30]Gotz J,Chen F,van Dorpe J,et al.Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Ap 42 fibrils[J].Science,2001,293(5534):1491-5.
[31]Ferrari A,Hoerndli F,Baechi T,et al.P-Amyloid induces paired helicalfilament-like tau filaments in tissue culture[J].J Biol Chem,2003,278(41):40162-8.
[32]Olney J W,Wozniak D F,Farber N B.Excitotoxic neurodegeneration in Alzheimer disease.New hypothesis and new therapeutic strategies[J].Arch Neurol,1997,54(10):1234-40.
[1]张志灯,曹治云,郑腾,等.改良的大鼠脑组织总RNA抽提方法[J].生物技术通讯,2006,17(5):760-1.
[2]Kang J,Lemaire H G,Unterbeck A,et al.The precursor of Alzheimer's disease amyloid Aβ protein resembles a cellsurface receptor[J].Nature,1987,325(6106):733-6.
[3]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004:18(1):22-26.
[4]韩柏,唐荣华,王锋,等.丹参大黄合剂对拟老年痴呆大鼠学习记忆能力及海马β淀粉样前体蛋白(APP)、早老素1(PS1)表达的影响[J].中华临床医师杂志,2008,2(8):912-7.
[1]Wengarten M.D,Lockwood A H,HWO S Y,et al.A protein factor essential for microtubule assembly[J].Proc Natl AcADSci USA,1975,72:1858-62.
[2]Grundke-Qbali,QBAL K,QUINLAN M,et al.Microtubule associated protein tau.a component of alzheimer paired helical filaments[J].J Biol Chem,1986,261:6084-9.
[3]Cleveland DW,Hwo SY,Kirschner MW.Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly[J].J Mol Bio,1977,116(2):227-47.
[4]Arrasate M,Perez M,Avila J.Tau dephosphorylation at tau-1 site correlates with It ' s association to cell membrane[J].Neurochem Res,2000,25(1):43-50.
[5]Avila J,Lucas JJ,Perez M,et al.Role of tau protein in both physiological and pathological conditions[J].Physiol Rev,2004,84(2):361-84.
[6]Thomas F,Jochen E,Roland B.Tau-mediated cytotoxicity in a pseudohyper-phosphorylation model of Alzheimer's Disease[J].J Neuroscience,2002,22(22):9733-41.
[1]Jeohn GH,Cooper CL,Wilson B,et al.P38 MAPkinase is involved in Lipopoly-saccharide -induced dopaminergic neuronal cell death in rat mesencephalic neuron-glia cultures [J].Anil.N.Y.Acad.Sci,2002,962:332-46.
[2]Flad HD,Loppnow H,Rietschel ET,et al.Agonists and antagonists for lipopoly-saccharide -induced cytokines[J].Immunobiology,1993,187(3-5):303-16.
[3]Grau GE,Frei K,Piguet PF,et al.Interleukin 6 production in experimental cerebral malaria:modulation by anticytokine antibodies and possible role in hypergammaglobulinemia[J].Exp Med,1990,172(5):1505-8.
[4]Heinzel FP.The role of IFN-gamma in the pathology of experimental endotoxemia[J].Immunol,1990,145(9):2920-4.
[5]Heinrich PC,Castell JV,Andus T.Interleukin-6 and the acute phase response[J].Biochem,1990,265(3):621-36.
[6]Mackenzie IR.Anti-inflammatory drugs and Alzheimer-type pathology in aging[J].Neurology,2000,54(3):732-4.
[7]Sheng JG,Mrak RE,Rovnaghi CR,et al.Human brain S100 beta and S100 beta mRNA expression increases with age:Pathogenic implications for Alzheimers disease[J].Neurobiol Aging,1996,17(3):359-63.
[8]Li Y,Liu L,Kang J,et al.Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression[J].J Neurosci,2000,20(1):149-55.
[9]Arvin B,Neville LF,Barone FC,et al.Brain injury and inflammation:a putative role of TNF alpha[J].Ann NY Acad So,1995;765:62-71.
[10]Benvenlste EN.Inflammatory cytokines within the central nervous system:sources,function,and mechanism of action[J].Am J Physiol,1992;263:11-16.
[11]Tarkowski E,Blennow K,Wallin A,et al.Intracerebral production of tumor necrosis factor-alpha,a local neuro protective agent,in Alzheimer disease and vascular dementia[J].J Clin Immunol,1999,19(4):223-30.
[12]Opal SM,Wherry JC,Grint P.Interleukin-10:potential benefits and possible risks in clinical infectious diseases[J].Clinical infectious diseases,1998,27(6):1497-507.
[13]Pajkrt D,Camoglio L,Tiel-van Buul MC,et al.Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia:effect of timing of recombinant human IL-10 administration[J].J Immunol,1997,158(8):3971-7.
[14]VanderPoll T,Jansen PM,Montegut WJ,et al.Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia[J].J Immunol,1997,158(4):1971-5.
[15]Hess PJ,Seeger JM,Huber TS,et al.Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factor-dependent murine model of acute visceral ischemia[J].J Vasc Surg,1997,26(1):113-8.
[16]Engles RE,Huber TS,Zander DS,et al.Exogenous human recombinant interleukin-10 attenuates hindlimb ischemia-reperfusion injury[J]J Surg Res,1997,69(2):425-8.
[17]Aste-Amezaga M,Ma X,Sartori A.et al.Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10[J].J Immunol,1998,160(12):5936-44.
[18]Brown CY,Lagnado CA,Vadas MA,et al.Differential regulation of the stability of cytokine mRNAs in Hpopolysaccharide-activated blood monocytes in response to interleukin-10[J].J Biol Chem,1996,271(33):20108-12.
[1]韩德五.肝脏病理生理学[M].太原:山西高校联合出版社,1992,136.
[2]Richman LK,Klingenstein R J,Richman JA,et al.The murine Kupffer cell.I.Characterization of the cell serving accessory function in antigen-specific T cell proliferation[J].J Immunol,1979,123(6):2602-9.
[3]Murray-Lyon IM,Davidson AR,Rake MO,et al.Hepatic scintiscanning in fulminant hepatic failure[J].Br J Radiol,1973,46(541):30-3.
[4]Naito M,Hasegawa G,Takahashi K.Development,differentiation and maturation of Kupffer cells[J].Microsc Res Tech,1997,39(4):350-64.
[5]Takezawa R,Watanabe Y,Akaike T.Direct evidence of macrophage differentiation from bone marrow cells in the liver:a possible origin of Kupffer cells[J].J Biochem Tokyo,1995,118(6):1175-83.
[6]Decker K.The response of liver macrophages to inflammatory stimulation[J].Keio J Med,1998,47(1):1-9.
[7]Reynolds JV,Murchan P,Redmond HP,et al.Failure of macrophage activation in experimental obstructive jaundice:association with bacterial translocation[J].Br J Surg,1995,82:534-38.
[8]Su L.Lipopolysaccharides in liver injury:molecular mechanisms of Kupffer cell activation[J].Am J Physiol Gastrointest Liver Physiol,2002,283(2):G256-65.
[9]Mochida S,Ohta Y,Ogata I.Fujiwara K.Gut-derived substances in activation of hepatic macrophages after partial hepatectomy in rats[J].J Hepatol,1992,16(3):266-72.
[1]黎君友,于燕,郝军,等.分光光发法测定血和小肠组织二胺氧化酶活性[J].氨 基酸和生物资源,1996,18(4):28-30.
[2]Saadia R,Schein M,MacFarlane C,et al.Gut barrier function and the surgeon[J].Br J Surg,1990,77:487-92
[3]韩德五.肠源性内毒素血症与肝病--肝衰竭的IETM学说.北京:中国科学技术出版社.2004,78-89.
[4]Navaratnam RL,Morris SE,Traber DL,et al.Endotoxin(LPS)increases mesenteric vascular resistance(MVR) and bacterial translocation(BT)[J].J Trauma,1990,30:1104-15.
[5]李晓芳.严重烧伤后胃肠道功能障碍的机制和防治[J].世界华人消化杂志,2006,14:888-93.
[6]Zhang H,Li Y,Wang S,et al.LPS-induced NF-kappa B activation requires Ca~(2+) as a mediator in isolated pancreatic acinar cells of rat[J].Chin Med J(Engl),2003,116:1662-7.
[7]Roland CR,Coss JA,Mangino MJ,et al.Autoregulation by eicosanoids of human Kupffer cell secretory products[J].Ann Sueg,1994,219:389-99.
[8]Chakravortty D,Kumark SN.Modulation of barrier function of small intestinal epithelial cells by lamina propria fibroblasts in response to lipopolysaccharide:Possible role in TNF-α in inducing barrier dysfunction[J].Microbiol Immunol,1999,43(6):527-33.
[9]Souba WW,Herskowitz K,Klimberg VS,et al.The effects of sepsis and endotoxemia on gut gultamine metabolism[J].Ann Surg,1990,211:543-51.
[10]Dudricr PS,Salloum RM,Copeland EM,et al.The early response of jejounal brush border glutamine transporter to endotoxemia[J].J Surg Res,1992,52:372-7.
[11]Koshi R,David S,Mathan Ⅵ,et al.Enteric vascular endothelial response to bacterial endotoxin[J].Int J Exp Path,1993,74:539-601.
[12]Libemaann TA,Baltimore D.Activation of interleukin-6 gene expression through the NF-KB transcription factor[J].Mol Cell Biol,1990,10(5):2327-34.
[13]余佩武,肖光夏,府伟灵,等.血小板活化因子在烧伤大鼠早期肠源性内毒素血症发病中的作用[J].中华医学杂志,1999,79(2):136-8.
[1]王琦,任东青,邝芳,等.脉冲式电磁辐射对大鼠血脑屏障影响的量效关系[J].疾病控制杂志.2003,7(5):401-4.
[2]Gonzalez-Nhriscal L,BetanzosA,lava P,etal.Tightjunctionproteins[J].Progress in Biophysics & Molecular Biology,2003,81:41-44.
[3]Lapierre LA.The molecular structure of the tightjunction[J].Advanced Drag Delivery Reviews,2000,41:255-64.
[4]Nusrat A,Parkos CA,Verkade P,et al.Tight junction are membrane microdomains[J].J Cell Sci,2001,113(Pt10):1771-81.
[5]彭镜,尹飞.血脑屏障连接复合体与脑损伤[J].国外医学.神经病学分册,2005,32(1):19-22.
[6]Stamatovic SM,Shakui P,Keep RF,et al.Monocyte chemoattractant protein-1regulation of blood-brain barrier permeability[J].J Cereb Blood Flow Metab,2005,25(5):593-606.
[7]彭镜,尹飞,甘娜.内毒素脂多糖对体外血脑屏障模型通透性的影响及其机制研究[J].中华医学杂志,2006,86(27):1924-6.
[8]彭镜,尹飞,李玉飞.川芎嗪对内毒素脂多糖诱导的体外血脑屏障模型通透性增高的保护作用及其机制[J].解剖学杂志,2007,30(5):594-6.
[9]Chavez-Bueno S,McCracken GH.Bacterial meningitis in children[J].Pediatr Clin North Am,2005,52(3):795-810.
[10]Elbashir SM,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J].Nature.2001,411(6836):494-8.
[11]程光,张翔,鲍炜,等.RNA干扰基因敲除MAGE-1在恶性胶质瘤U-87细胞中的初步研究[J].医学研究生学报,2006,19(4):292-7.
[12]杨翔云,张勇,赖小刚,等.人CLC-2基因小分子干扰RNA真核表达载体的构建和鉴定[J].医学研究生学报,2006,19(4):487-91.
[13]Tuschl T.Expanding small RNA interference[J].Nat Biotechnol,2002,20(5):446-8.
[14]Sin JI,Kim JJ,Zhang D,et al.Modulation of cellular responses by plasmid CD40L:CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4~+ T cell-mediated protective immunity against herpes simplex virus type 2 in vivo[J].Hum Gene Ther,2001,12(9):1091-102.
[15]褚晓源,王杰军,陈龙邦,等.小鼠肠癌RNA转染mML-12修饰的树突状细胞诱发特异性细胞毒性T淋巴细胞的研究[J].医学研究生学报,2007,20(1):15-19.
[1]Wegiel J,Imaki H,Wang KC,et al.Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPswtg mice[J].Brain Res,2004,1022(1-2):19-29.
[2]Malm TM,Koistinaho M,P(a|¨)repalo M,et al.Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice[J].Neurobiol Dis,2005,18(1):134-42.
[3]Kim SU,de Vellis J.Microglia in health and disease[J].J Neurosci Res,2005,81(3):302-13.
[4]Saito T,Iwata N,Tsubuki S,et al.Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation[J].Nat Med,2005,11(4):434-9.
[5]Simard AR,Soulet D,Gowing G,et al.Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease[J].Neuron,2006,49(4):489-502.
[6]Cardona AE,Huang D,sasse ME,et al.Isolation of murine microglial cells for RNA analysis or flow cytometry[J].Nat Protoc,2006,1(4):1947-51.
[7]Giuhan D,Baker TJ.Characterization of ameboid microglia isolated from developing mammalian brain[J].J Neurosci,1986,6(8):2163-78.
[8]Giulian D,Li J,Barrel S,et al.Cell surface morphology identifies microglia 88 a distinct class of mononuclear phagocyte[J].J Neurosci,1995,15(11):7712-26.
[9]雷万龙,袁群芳,张怀波,等.啮缺血性半影区胶质细胞和神经元重组的形态学观察[J].中山医科大学学报,2002,23:29-32.
[10]Zhang ZG,Chopp M,Powers C.Temporal profile of microglial response following transient(2h) middle cerebral artery occlusion[J].Brain Res,1997,744:189-98.
[11]Ward SA,Ransom PA,Booth PL,et al.Characterization of ramified microglia in tissue culture 1 pinecytosis and motility[J].J Neurosci Res,1991,29(8):13-28.
[12]Vila M,Jackson Lewis V,Guegan C,et al.The role of glial cells in Parkinson's disease [J].Curr Opin Neurol,2001,14(4):483-9.
[13]Kerschensteiner M,Stadelmann C,Dechant G,et al.Neurotrophic cross-talk between the nervous and immune systems;implications for neurological diseases[J].Ann Neurol,2003,53(3):292-304.
[14]Blasi E,Barluzzi R,Bocchini V,et al.Immortalization of murine microglial cells by a v-mf/v-myc carrying retrovirus[J].J Neuroimmunol,1990,27:229-37.
[1]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[2]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[3]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].ProgBrainRes,2001,132:555-65.
[4]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke[J].Ernst Schering Res Found Workshop,2002,105:32.
[5]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[6]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[7]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[8]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation and human microglial activation[J].Glia,2006,53:233-40.
[9]Xia MQ,Qin SX,Wu LJ.et al.Immunohistochemical study of the 5-chemokine receptors CCR3 and CCR5 and their figands in normal and Alzheimefs disease brains[J].Am J Pathol,1998,153:31-7.
[10]Xia MQ,Bacskai BJ,Knowles RB,et al.Expression of the chemokine receptor CXCR3on neurons and the elevated expression of its ligand IL-10 in reactive astrocytes:fnvitro ERK112activation and role inAlzheimer's disease[J].J Neuroimmunol,2000,108:227-35.
[11]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell iniury via a nitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[12]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease[J].Biochim Biophys Acta,1997,1362:77-86.
[13]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[14]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[15]Frautschy SA,Cole GM,Baird A.Phagocytosis and deposition of vascular 5-amyloid in rat brains injected with Alzheimer β amyloid[J].Am J Pathol,1992,140:1389-99.
[16]Weldon DT,Rogers SD,Ghilardi JR,et al.Fibrillar B-amyloid induces microglial phagocytosis,expression of inducible nitric oxide synthase and loss of a select population of neurons in the rat CNS in vivo[J].J Neurosci,1998,18:2161-73.
[17]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid p protein deposition[J].ActaNeuropathol(Bed),1997,94:316-22.
[18]Meda L,Cassatella MA,Szendrei GI,et al.Activation of mi croglial cells by B-amyloid protein and interferon-γ[J].Nature,1995,374:647-50.
[19]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[20]Lazar G.The reticuloendothelial-blocking effect of rare earth metals in rats.[J].J Reticuloendothel Soc,1973,13(3):231-7.
[21]Husztik E,Lazar G,Parducz.Electron microscopic study of Kupffer phagocytosis blockade induced by gadolinium chloride[J].Br J Exp pathol,1980,61(6):624-30.
[22]Roland CR,Mangino MJ,Flye MW.Lanthanide blockade of antigen-presenting cells suppresses lymphocyte proliferation by inducing nitric oxide synthesis[J].J Surg Res,1993,54(5):401-10.
[23]Mizgerd JP,Molina RM,Stearns RC,et al.Gadolinium induces macrophage apoptosis[J].J Leukoc Biol,1996,59(2):89-95.
[24]Laskin D L,Gardner C R,Price V F,et al.Modulation of macrophage function ingablogates the acute hepatotoxicity of acetaminophen[J].Hepatology,1995,21(4):1045-50.
[25]Roland C R,Naziruddin B,Mohanakumar T,et al.Gadolinium chloride inhibits Kupffer cell nitric oxide synthase(iNOS) induction[J].J Leukoc Biol,1996,60(4):487-92.
[26]Knecht K T,Adachi Y,Bradford B U,et al.Free radical adducts in the bile of rats treated chronically with intragastric alcohol:inhibition by destruction of Kupffer cells[J].Mol Pharmacol,1995,47(5):1028-34.
[27]Rai R M,Zhang J X,Clemens M G,et al.Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro-and anti-inflammatory cytokines[J].Shock,1996,6(4):243-7.
[28]Vollmar B,Ruttinger D,Wanner G A,et al.Modulation of kupffer cell activity by gadolinium chloride in endotoxemic rats[J].Shock,1996,6(6):434-41.
[1]Stoll G,J ander S.The role of microglia and macropha ges in the pathophysiology of the CNS[J].ProgNeurobiol,1999,58(3):233-47.
[2]Pyeongiae L,Jongseok L,Sunshin K,et al.NO as an autocrine mediator in the apoptosis of activated microglialcells:correlation between activation and apoptosis of microglial cells[J].Brain Research,2001,892(2):380-5.
[3]Ferrari D.Chiozzi P,Falzoni S,et al.ATP-mediated cytotoxicity in microglial cells [J].Neuropharmacology,1997,36(9):1295-301.
[4]Xiao BG,Bai XF,Zhang GX,et al.Transforming growth factor-betal induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J].Neurosci Lett,1997,226(2):71-4.
[5]Ogata T,Schubert P.Programmed cell death in rat microglia is controlled by extracellular adenosine[J].NeuroseiLett,1996,218(2):91-4.
[6]Kingharn P J,Pocock JM.Microglial apoptosis induced by chromogranin A is mediated by mitochondrial depolarisation and the permeability transition but not by cytochrome c release.[J].J Neuro Chem,2000,74(4):1452-62.
[7]Jung DY,Lee H,Jung BY,et al.TLR4,but not TLR2,signals autoregulatory apoptosis of cultured microglia:a critical role of IFN-beta as a decision maker[J].J Immunol,2005,174(10):6467-76.
[8]Hu S,Sheng WS,Lokensgard JR,et al.Morphine induces apoptosis of human microglia and neurons.[J].Neuroscience Letters,2002,42(6):829-36.
[1]Jin Y,Fan Y,Yah EZ,et al.MAP kinase superfamily in amyloid β-protain fragment 25-35 induced inflammation and apoptosis in rat hippocampus in vivo Chin[J].J Pharmacol Toxicol,2005,19(3):161-8.
[2]Sundaratajan S,Gambea,Victor NA.et al.Peroxisome proliferator activated receptorgamma ligands reduce inflammation and infarction size in transient focal ischemia [J].Neuroscience,2005,130:685-696.
[3]Widmann C,Gibson S,Jarpe MB,et al.Mitogen-activated protein kinase:conservation of a three-kinase module from yeast to human[J].Physiol Rev,1999,79(1):143-180.
[4]Jeohn GH,Cooper CJ,Wilson B,et al.p38 MAP kinase is involved in Lipopoly-saccharide -induced dopaminergie neuronal cell death in rat meseneephalic neuron-glia cultures [J].Ann NY Acad Sci,2002,962:332-46.
[5]Bhat NR,Zhang P,Lee JC,et al.Extracellular signal-regulated-kinase and p38subgroups of mitogen-activated protein kinases regulateinducible nitric oxide synthase and tumor necrosis factor gene expressionin endotoxin-stimulated primary glial cultures[J].J Neurosci,1998,18:1633-41.
[6]Tikka T,Fiebich BI,Goldsteins G,et al.Minocycline,a tetracycline derivative,is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia [J].J Neurosci,2001,21:2580-8.
[7]Sundararajan S,Gamboa JL,Victor NA,et al.Peroxisome proliferator activated receptor gamma ligands reduce inflammation and infarction size in transient focal ischemia [J].Neuroscience,2005,130:685-96.
[8]Swatton JE,SellersLA,FaunRL,et al.Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain[J].Eur J Neurosci,2004.19(10): 2711-9.
[9]Sun A,Liu M,Nguyen XV,et al.P38 MAP kinase is activated at early stages in Alzheimer's disease brain[J].Exp Neural,2003,183(2):394-405.
[10]Otth C,Mendeza-Naranjo A,Mujica L,et al.Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease[J].Neuro report,2003,14(18):2403-9.
[11]Schechter R,Beju D,Miller KE.The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse[J].Biochem Biophys Res Commun,2005,34(4):979-86.
[12]Foey AD,Parry SL,Williams LM,et al.Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha:role of the p38 and p42/44 mitogen-activated protein kinases[J].J Immunol,1998,160(2):920-8.
[13]Swantek JL,Cobb MH,Geppert TD.Jun N-terminal kinase/stress-activated protein kinase(JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha(TNF-alpha) translation:glucocorticoids inhibit TNF-alpha translation by blocking JNK/ SAPK[J].Mol Cell Biol,1997,17(11):6274-82.
[14]Jians Y,Liu AN,Huang QB,et al.p38 MAPK signal is necessary for TNF-α gene expression in RAW cells[J].Acta Biochim Biophys Sin,1999,31(1):9-15.
[15]Minogue AM,Schmid AW,Fogarty MP,et al.Activation of the c-Jun N-terminal kinase signaling cascade mediates the efect of amyloid-beta on long term potentiation and cell death in hippocampus:a role for interleukin-1beta[J].Bid Chem,2003,278(30):27971-80.
[16]Shoji M,wakami N,Takeuchi S,et al.JNK activation is associate with intracellular beta-amyloid accumulation[J].Brain Res Mol Brain Res,2000,85:221-33.
[17]Savage MJ,Un YG,Cialela JR,et al.Activation of c-Jun Nterminal kinase and p38 in an Klzheimerg disease model is associated with amyloid deposition[J].Neurosci,2002,22:3376-85.
[18]Abramo C,Massone S,Zingg JM,et al.Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death[J].Biochem,2005,391:693-8.
[19]Jiang Y,Liu AN,Zhang L,et al.Activation of p38 mitogen-activated protein kinasein duced by lipopolysaccharide and its the in TNF-α geneex pression[J].J Med Coll PL A,1999,14(2):138-43.
[20]Zhao M,Liu YW,Liu AH,et al.Signal transduction in TNF-α inducted c-jun geneex pression[J].Acta Biochim Biophys Sin,2000,32(3):59-65.
[21]Guan Z,Baier LD,Morrison AR.p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1beta[J].J Biol Chem,1997,272(12):8083-9.
[22]Takahashi.S,Kapas.I,Fang J,et al.Somnogenic relationships between tumor necrosis factor and interleukin 1[J].Am J Physiol,1999,276:1132-40.
[23]Seon H.Kim,Carolyn J,Smith,et al.Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1β production[J].Neurobiology of Aging,2004,25:431-9.
[1]Mark PM.NF-κB in the survival and plasticity of neurons[J].Neurochemical Res,2005,30(6/7):883-93.
[2]陈彬,罗勇.血管内皮细胞中核因子-κB对靶基因的转录调节[J].国外医学脑血管疾病分册,2004,12(12):936-9.
[3]颜因,罗勇.脑缺血炎症反应与星形胶质细胞的关系[J].中国康复理论与实践,2006,12(10):867-70.
[4]何兰英,罗勇.脑缺血再灌注后神经元中核因子-κB对靶基因的转录调节[J].神经疾病与精神卫生,2007,7(1):45-48.
[5]Karin M.How NF-kappaB is activated:the role of the IkappaB kinase(IKK) complex [J].Oncogene,1999,18(49):6867-74.
[6]Kaltschmidt B,Uherek M,Volk B,et al.Transcription factor NF-κB is activated in primary neurons by amyloid β peptides and in neurons surrounding early plaques from patients with Alzheimer disease[J].Proc Natl Acad Sci USA,1997,94:2642-7.
[7]Barger SW,Mattson MP.Tumor necrosis factor α and β protect neurons against amyloid β-peptide toxicity:evidence for involvement of κB-binding factor and attenuation of peroxide and Ca~(2+) accumulation[J].Proc Natl Acad Sci USA,1995,92:9328-32.
[8]Akama KT,Albanese C,Pestell RG,et al.Amyloidβpeptide stimulates nitricoxide production in astrocytes through an NF-κB-dependent mechanism[J].Proc Natl Acad Sci USA,1998,95:5795-800.
[9]Lee HJ,Kim SH,Kim KW,et al.Antiapoptotic role of NF-κB in the auto-oxidized dopamine-induced apoptosis of PC12 cells[J].J Neurochem,2001,76:602-9.
[10]Panet H,Barzilai A,Daily D,et al.Activation of nuclear transcription factor kappa B(NF-κB) is essential for dopamine-induced apoptosis in PC12 cells[J].J Neurochem,2001,77:391-8.
[11]Mattson MP,Camandola S.NF-κB in neuronal plasticity and neuro degenerative disorders[J].J Clin Invest,2001,107:247-54.
[1]林明群,张宗梁.巨噬细胞免疫调节信号-PKA与PKC对MAPK信号通路的调节[J].生物化学和生物物理学报,1999,31(6):701-6.
[2]Shames B D,Selzman C H,Pulido E J,et al.LPS-Induced NF-kappaB activation and TNF alpha release in human monocytes are protein tyrosine kinase dependent and proten kinase C independent[J].J Surg Res,1999,83(1):69-74.
[3]White J E,Lin H Y,Davis F B,et al.Differential induction of tumor necrosis factor alpha and manganese superoxide dismutase by endotoxin in human monocytes:role of protein tyrosine kinase,mitogen-activated protein kinase,and nuclear factor kappaB[J].J Cell Physiol,2000,182(3):381-9.
[4]Giles E H,Fiona J L,Hilmar B,et al.Naclear calcium signaling controls CREB-mediated gene expression triggered by synaptic actitity[J].Nature Neuroscience,2001,4(3):261-7.
[5]Elliott AC.Recent developments in non-excitable cell calcium entry[J].Cell Calcium,2001,30(2):73-93.
[6]金胜威,张力,叶笃筠等.脂氧素对脂多糖诱导的巨噬细胞游离钙浓度变化及活性氧的影响[J].中国病理生理杂志,2005,21(8):1651.
[7]肖殿模,吕文戈,王小鲁等.内毒素对细胞钙摄取及胞浆游离钙浓度的影响[J].中国危重病急救医学,1992,4(2):71-3.
[8]Kawahara M,Kuroda Y.Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein:channel formation and disruption of calcium homeostasis[J].Brain Res Bull,2000,53(4):389-97.
[9]Suh YH.An etiological role of amyloidogenic carboxy-terminat fragments of the beta-amyloid precursor protein in Alzheimer's disease [J].J Neurochem,1997,68;1781-91.
[10]Ca C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chroinc application of beta-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203:61-65.
[11]Guo Q,Robinson N,Mattson M.Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant prusenilin-1 by activation of NF-kappa B and stabilization of calcium homeostasis [J].J Biol Chem,1998,273:12341-51.
[12]Whitson JS,Appel SH.Neurotoxicity of amyloid-beta protein in vitro is not alerted by calcium channel blockade [J].Neurobiol Aging,1995,16:5-10.
[1]Small GW,Rabins PV,Barry PP,et al.Diagnosis and treatment of Alzheimer disease and related disorders.Consensus statement of the American Association for Geriatric Psychiatry,the Alzheimer's Association,and the American Geriatrics Society[J].JAMA,1997,278(16):1363-71.
[2]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neual,1999,56(9):1121-3.
[3]Olson RE,Copeland RA.Progress towards testing the amyloid hypothesis:inhibitors of APP processing[J].Curr Opin Drug Discov Devel,2001,4(4):390-401.
[4]Mcquade R,Young A H.Future therapeutic targets in mood disorders:the glucocorticoid receptor[J].Br J Psychiatry,2000,177(2):390-5.
[5]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[6]李权益,高薮幔.分子医学-艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-80.
[7]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:117.
[8]田金洲,时晶,程龙,等.阿尔茨海默病患者脑淀粉样血管病变[J].中华老年医学杂志,2003,22(11):708-10.
[9]Cacabelos R.The application of functional genomics to Alzheimer's disease[J].Pharmcaogenomics,2003,4(5):597-621.
[10]Hardy J,Dennis J.The amyloid hypothesis of Alzheimer's disease:progress and problems on the roADto therapeutics[J].Science,2002,297(5508):353-6.
[11]YamagataK,UrakamcK,IredaK,et al.High expression of apolipo proteinE mRNA in the brains with sporadic Alzheimer's disease[J].Dement Geriatr CognDisord,2001,12(2):57-62.
[12]Raygani AV,Zahrai M,Raygani AV,et al.Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran,Iran[J].Neurosci Lett,2005,375(1):1-6.
[13]TrommerBL,Shah C,Yun SH,et al.ApoE isoform-specific effects on LTP:block adeby oligomeric amyloid-betal-42[J].NeurobiolDis,2005,18(1):75-82.
[14]Trittmatter WJ.Apolipoprotein E and Alzheimer's disease:signal transduction mechanisms[J].Biochem SocSymp,2001,(67):101-9.
[15]Ezquerra M,Carnero C,Blesa R,et al.Anovel presenilinl mutation(Leu166Arg)associated withearly onset alzheimer disease[J].J Arch Neurol,2000,57(4):485-8.
[16]Queralt R,Ezquerra M,Castell vi M,et al.Detection of the presenilin 1 genemutation (ML39T) in early onset familial Alzheimer disease in Spain [J].Neurosci Lett,2001,299(3):239-41.
[17]JoannaL,JankowskyJL,FadaleDJ,et al.Mutant presenilins specifically elevate the levels of the 42residue beta-amyloid peptidein vivo:evidence for augmentation of a42-specific gamma secretase [J].Hum Mol Genet,2004,13(2):159-70.
[18]Alvarez V,Alvarez R,Lahoz CH,et al.Association between an alpha(2) macroglobulin DNApolymorphismandlate-onset alzheimer's disease [J].Biochem Biophys ResCommun,1999,264(1):48-50.
[19]KosterMN,DermautB,CrutsM,et al.The alpha2-macroglobulingenein AD:apopulation-based study and meta-analysis [J].Neurology,2000,55(5):678-84.
[20]ZappisM,CittadellaR,Mannal,et al.Genetic association of alpha2-macroglobul in polymorphisms with ADin southern Italy [J].Neurology,2002,59(5):756-8.
[21]WangJZ,Grundke-IqbalK.Glycosylation of microtubule-associated protein tau:an abnormal posttranslational modification in Alzheimer's disease [J].Nat Med,1996,2(8):871-5.
[22]Mayeux R,Lee JH,Romas SN,et al.Chromosome-12 mapping of late-onsef alzheimer disease among Caribbean Hispanics [J].Am J Hum Genet,2002,70(1):237-43.
[23]HerzJ.LRP:Abright beaconat the blood-brain barrier [J].JClinInvest,2003,112(10):1483-5.
[24]Hyoung Lee,Gemma C,Mark S,et al.Challenging the amyloid cascade hypo-thesissenile plaques and amyloid-P asprotective adaptations to Alzheimer disease [J].AnnNYAcadSci,2004,1019:1-4.
[25]Glenner GG,Wong CW.Alzheimer's disease:initial report of the purification and characterization of an ovelcerebro vascular amyloid protein [J].Biochem Biophys Res Commun,1984,120(3):885-90.
[26]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis [J].Science,1992,256(5054):184-5.
[27]Kang J,Lemaire H G,Unterbeck A,et al.The precursor of Alzheimer's disease amyloid A4 protein resembles a cellsurface receptor [J].Nature,1987,325(6106):733-6.
[28]Buxbaum JD,Liu KN,Luo Y,et al.Evidence that tumor necrosis factor a converting enzyme is involved in regulated a-secretase cleavage of the Alzheimer amyloid protein precursor [J].J Biol Chem,1998,273(43):27765-7.
[29]Vassar R,Bennett BD,Babu-Khan S,et al.β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE [J].Science,1999,286(5440):735-41.
[30]Farzan M,Schnitzler CE,VasilievaN,et al.BACE2,aβ-secretase homolog,cleaves at the β site and within the amyloid-p region of the amyloid-P precursor protein [J].Proc Natl AcADSci USA,2000,97(17):9712-7.
[31]Borchelt D R,ThinakaranG,Eckman CB,et al.Familial Alzheimer's disease-linked presenilin1variantselevate Aβ-42/1-40 ratio in vitro and in vivo [J].Neuron,1996,17(5):1005-13.
[32]Herreman A,Serneels L,Annaert W,et al.Total inactivation of g-secretase activity in presenilin-deficientembryonicstem cells [J].Nat Cell Biol,2000,2(7):461-2.
[33]Eckman CB,Mehta ND,Crook R,et al.A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of Aβ 42(43) [J].Hum Mol Genet,1997,6(12):2087-9.
[34]Suzuki N,Cheung TT,Cai XD,et al.An increased percentage of long amyloid b-protein secreted by familial amyloid β protein precursor (β APP717) mutants.Science,1994,264(5163):1336-40.
[35]Kwok JB,Li QX,Hallupp M,et al.Novel Leu723Pro amyloid precursor protein mutation increases amyloid b42(43) peptide levels and induces apoptosis.Ann Neurol,2000,47(2):249-53.
[36]Cai XD,Golde TE,Younkin S G.Release of excess amyloid b protein from a mutant amyloid b protein precursor [J].Science,1993,259(5094):514-16.
[37]Haass C,Hung AY,Selkoe DJ,et al.Mutations associated with alocus for familial Alzheimer's disease resultin alternative processing of amyloid b-protein precursor [J].J Biol Chem,1994,269(26):17741-8.
[38]Scheuner D,Eckman C,Jensen M,et al.Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease [J].Nat Med,1996,2(8):864-70.
[39]De Strooper B,Saftig P,Craessaerts K,et al.Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].Nature,1998,391(6665):387-90.
[40]Mohajeri MH,Saini KD,Nitsch RM.Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology [J].J Neural Transm,2004,111(3):413-25.
[41]Gillespie SL,Golde TE,Younkin SG Secretory processing of the Alzheimer amyloid b/A4 protein precursor is increased by protein phosphorylation [J].Biochem Biophys Res Commun,1992,187(3):1285-90.
[42]Nitsch RM,Slack BE,Wurtman RJ,et al.Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinicacetyl choline receptors [J].Science,1992,258(5080):304-7.
[43]Villa A,Latasa M J,Pascual A.Nerve growth factor modulates the expression and secretion of β-amyloid precursor protein through different mechanisms in PC 12 cells [J].J Neurochem,2001,77(4):1077-84.
[44]Racchi M,Mazzucchelli M,Porrello E,et al.Acetylcholinesterase inhibitors:novel activities of old molecules [J].Pharmacol Res,2004,50(4):441-51.
[45]Simons M,Keller P,De Strooper B,et al.Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons.Proc Natl AcADSci USA,1998,95(11):6460-4.
[46]Yankner BA,Dawes LR,Fisher S,et al.Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.Science,1989,245(4916):417-20.
[47]Frautschy SA,Baird A,Cole G M.Effects of injected Alzheimer β-amyloid cores in rat brain [J].Proc Natl AcADSci USA,1991,88(19):8362-6.
[48]Pike CJ,Walencewicz AJ,Glabe C G,et al.In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity [J].Brain Res,1991,563(1-2):311-4.
[49]Lesne S,Koh M T,Kotilinek L,et al.A specific amyloid-b protein assembly in the brain impairs memory [J].Nature,2006,440(7082):352-7.
[50]Verdier Y,Zarandi M,Penke B.Amyloid b-peptide interactions with neuronal and glial cell plasma membrane:bindingsites and implications for Alzheimer's disease.J Pept Sci,2004,10(5):229-48.
[51]Kim HS,Lee J H,Lee J P,et al.Amyloid b peptide induces cytochrome C release from isolated mitochondria [J].Neuroreport,2002,13(15):1989-93.
[52]Probst A,Langui D,Ulrich J.Alzheimer's disease:a description of the structural lesions[J].BrainPathol,1991,1(4):229-39.
[53]Meda L,Bernasconi S,Bonaiuto C,et al.β-amyloid (25-35) peptide and IFN-g synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells [J].J Immunol,1996,157(3):1213-8.
[54]Mark R J,Hensley K,Butterfield D A,et al.Amyloid b-peptide impairs ion-motive ATPase activities:evidence for a role in loss of neuronal Ca2+ homeostasis and cell death [J].J Neurosci,1995,15(9):6239-49.
[55]Davidson RM,Shajenko L,Donta TS.Amyloid β-peptide(ApP) potentiates a nimodipine-sensitive L-type barium conductance in NlE-115 neuroblastoma cells [J].Brain Res,1994,643(1-2):324-7.
[56]Mattson MP,Cheng B,Davis D,et al.β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity [J].J Neurosci,1992,12(2):376-89.
[57]Behl C,Davis JB,Lesley R,et al.Hydrogen peroxide mediatesamyloid b protein toxicity [J].Cell,1994,77(6):817-27.
[58]Butterfield DA,Hensley K,Harris M,et al.beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion:implications to Alzheimer's disease [J].Biochem Biophys Res Commun,1994,200(2):710-5.
[59]Cafe C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chronic application of β-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203(1):61-65.
[60]Mattson MP.Pathways towards and away from Alzheimer's disease [J].Nature,2004,430(7000):631-639.
[61]Casley CS,Land JM,Sharpe MA,et al.β-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons [J].Neurobiol Dis,2002,10(3):258-67.
[62]Blass JP.Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? [J].J Neurosci Res,2001,66(5):851-6.
[63]Takashima A,Honda T,Yasutake K,et al.Activation of tau protein kinase I/glycogen synthase kinase-3b by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons [J].Neurosci Res,1998,31(4):317-23.
[64]Gotz J,Chen F,van Dorpe J,et al.Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Ap 42 fibrils [J].Science,2001,293(5534):1491-5.
[65]Ferrari A,Hoerndli F,Baechi T,et al.β-Amyloid induces paired helical filament-like tau filaments in tissue culture [J].J Biol Chem,2003,278(41):40162-8.
[66]Olney J W,Wozniak D F,Farber N B.Excitotoxic neurodegeneration in Alzheimer disease.New hypothesis and new therapeutic strategies [J].Arch Neurol,1997,54(10):1234-40.
[67]Iwata N,Tsubuki S,Takaki Y,et al.Metabolic regulation of brain Ab by neprilysin [J].Science,2001,292(5521):1550-2.
[68]Perez A,Morelli L,Cresto JC,et al.Degradation of soluble amyloid b-peptides 1-40,1-42,and the Dutch variant 1-40 by insulin degrading enzyme from Alzheimer disease and control brains [J].Neurochem Res,2000,25(2):247-55.
[69]Nawrot B.Targeting BACE with small inhibitory nucleic acids-a future for Alzheimer's disease therapy? [J].Acta Biochim Pol,2004,51(2):431-44.
[70]Patey SJ.The role of heparan sulfate in the generation of Aβ [J].Drug News Perspect,2006,19(7):411-6.
[71]Steinhilb ML,Turner R S,Gaut J R.The protease inhibitor,MG132,blocks maturation of the amyloid precursor protein Swedish mutant preventing cleavage by b-secretase [J].J Biol Chem,2001,276(6):4476-84.
[72]Asai M,Hattori C,Iwata N,et al.The novel b-secretase inhibitor KMI-429 reduces amyloid b peptide production in amyloid precursor protein transgenic and wild-type mice [J].J Neurochem,2006,96(2):533-40.
[73]Lefranc-Jullien S,Lisowski V,Hernandez J F,et al.Design and characterization of a new cell-permeant inhibitor of the b-secretase BACE1 [J].Br J Pharmacol,2005,145(2):228-35.
[74]Zhang HY,Tang XC.Neuroprotective effects of huperzine A:new therapeutic targets for neurodegenerative disease [J].Trends Pharmacol Sci,2006,27(12):619-25.
[75]Soto C.Plaque busters:strategies to inhibit amyloid formation in Alzheimer's disease [J].Mol Med Today,1999,5(8):343-50.
[76]Smith JV,Luo Y.Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761 [J].J Alzheimers Dis,2003,5(4):287-300.
[77]Sierpina VS,Wollschlaeger B,Blumenthal M.Ginkgo biloba [J].Am Fam Physician,2003,68(5):923-6.
[78]Wang R,Yan H,Tang X C.Progress in studies of huperzine A,a natural cholinesterase inhibitor from Chinese herbal medicine [J].Acta Pharmacol Sin,2006,27(1):1-26.
[79]Schenk D,Barbour R,Dunn W,et al.Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse [J].Nature,1999,400(6740):173-7.
[80]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo [J].Exp Neurol,2000,163(2):388-91.
[81]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation [J].Neurochem Int,2001,39(526):341-8.
[82]Grammas P,Ovase R.Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain [J].Am J Pathol,2002,160 (5):1583-7.
[83]Hoozemans J,Veerhuis R,Janssen I,et al.The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia:implications for Alzheimer's disease [J].Brain Res,2002,951(2):218-26.
[84]O'Banion MK,Miller JC,Chang JW,et al.Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murineastrocyte cultures [J].J Neuro chem,1996,66(6):2532-40.
[85]Ho L,Pieroni C,Winger D,et al.Regionaldistribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease [J].J Neurosci Res,1999,57(3):295-303.
[86]Xiang Z,Ho L,Yemul S,et al.Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology [J].Gene Expr,2002,10(526):271-8.
[87]Webster SD,Yang AJ,Margol L,et al.Complement component C1q modulates the phagocytosis of A beta by microglia [J].Exp Neurol,2000,161(1):127-38.
[88]Shen Y,Lue L,Yang L,et al.Complement activation by neurofibrillary tangles in Alzheimer's disease[J].Neurosci Lett,2001,305(3):165-8.
[89]Bradt BM,Kolb WP,Cooper NR.Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide[J].J Exp Med,1998,188(3):431-8.
[90]McGeer EG,Yasojima K,Schwab C,et al.The pentraxins possible role in Alzheimer's disease and other innate inflammatory disease[J].Neurobiol Aging,2001,22(6):843-8.
[91]McGeer PL,Walker DG,Pitas RE,et al.Apolipoprotein E4(ApoE4) but not ApoE3 or ApoE2 potentiates beta-amyloid protein activation of complement in vitro[J].Brain Res,1997,749(1):135-8.
[92]KuoH,IngramDK,WalkerLC,et al.Similaritiesin theage-related hippocampalde position of periodicacid schiff-positive granules in the senescence-accelerated mouse P8 and C57BL/6 mousestrains[J].Neuroscience,1996,74:733-40.
[93]魏小龙,张永祥.老年性痴呆动物模型研究进展[J].中国药理学通报,2000,16:372-6.
[94]Hefti F,Dravid A,Hartikka J.Chronic in traventricular injections of NGF elevate hippocampal choline acetyl transfer as eactivity in adult rats with septo hippocam pallesions [J].BrainRes,1984,293:305-11.
[95]Miyarnoto M,Koto J,NarumiS,et al.Lesions of the rat basal fore brain leads to memory impairments in passive and active avoidance tasks[J].Brain Res,1985,328:97-104.
[96]Sofroniew MV,Pearson RCA.Degeneration of cholinergic neurons in the basal nucleus following kainicor N-methyl-D-asparticacid application to the cerebral cortex in the rat[J].BrainRes,1985,339:186-190.
[97]Fisher A,Hanin I.Potential animal models for senile dementia of Alzheimer's type,with emphasison AF64A-induced cholinotoxicity[J].Annu Rev Pharmacol Toxicol,1986,26:161-81.
[98]NabeshimaT.Trial to produce animal model of Alzheimer's disease by continuous infusion of beta-amyloid protein into the ratcerebral ventricle[J].Nihon Shinkei Seishin Yakurigaku Zasshi,1995,15:411-8.
[99]Alvarez XA,Miguel-Hidnlgo JJ,Fernandez-Novoa L,et al.Introhippocampal injections of the beta-amyloid 1-28 fragment induces behavior aldeficits in rats[J].Methods Find Exp Clin Pharmacol,1997,19(7):471-9,
[100]Florence AL,Gauthier A,Ponsar C,et al.An experimental animal model of aluminium overload[J].Neurodegeneration,1994,3:315-23.
[101]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004,18:22-26.
[102]罗焕敏,陈子晟.一种新的老年痴呆动物模型[J].中国老年学杂志,2003,23:179-82.
[103]Eilam D,Szechtman H,Faigon M,et al.Disintergration of the spatical organization of behavior in experiment alautoimmunede mentia [J].Neuroscience,1993,56:83-91.
[104]Moran PM,Higgins LS,Cordell B,et al.Age-related learning deficits in transgenic mice expressing the751-aminoacid isoform of human beta-amyloid precursor protein [J].Pro Natl AcADSci USA,1995,92:5341-5.
[105]Games D,Adams D,Alessandrini R,et al.Alzheimer-type neuro pathology in transgenic mice over expressing V717F B-amyloid precursor protein [J].Nature,1995,373:523-7.
[106]Hsiao K,Chapman P,Nilsen S,et al.Correlative memory deficits,AB elevation and amyloid plaques in transgenicmice [J].Science,1996,274:99-102.
[107]Selkoe DJ.Translating cell biology into therapeutic advances in Alzheimer's disease [J].Nature.1999 Jun 24;399(6738 Suppl):A23-31.
[108]Bullock R.New drugs for Alzheimer's disease and other dementias [J].Br J Psychiatry,2002,180:135-9.
[109]NabeshimaT,Yamada K.Development of anti-dementia drugs for Alzheimer's disease [J].AdvBehavBiol,2002,51:223-8.
[110]Wolson C,Perrault A,Moride Y,et al.Acase-control analysis of nonsteroidal anti-inflammatory drugs and Alzheimer's disease [J].Neuroepidemiology,2002,21:81-86.
[111]Simpkins JW,Green P,Gridley KE,et al.Role of Esteogen replacement therapy in memory enhancement and prevention of neuronal loss associated with Alzheimer's disease [J].Am J Med,1997,103:19-25.
[112]Pratico D,Uryu K,Leight S,et al.Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis [J].J Neurosci,2001,21:4183-7.
[113]Sano M,Ernesto C,Thomas RG,et al.Acontrolled trial of selegiline,a-tocopherol,or both as treatment for Alzheimer's disease [J].NewEngJMed,1997,336:1216-22.
[114]LiYM,XuM,LaiMT,et al.Photo activated β-secretase inhibitors directed to the activesite covalently label presenilinl [J].Nature,2000,405:689-94.
[115]Esler WP,Kimberly WT,Ostaszewski BL,et al.Transition-state analogue inhibitors of γ-secretase binds directly to pressenilin-1 [J].NatCellBiol,2002,2:428-34.
[116]Dovey HF,John V,Andereson JP,et al.Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain [J].JNeurochem,2001,76:173-81.
[117]Morgan D,Diamond DM,Gottschall PE,et al.Aβ peptide vaccination prevent smemory loss in an animal model of Alzheimer's disease [J].Nature,2000,408:982-5.
[118]Birminghan K,Frantz S.Set back to Alzheimer vaccine studies [J].NatMed,2002, 8:199-200.
[119]Atwood CS,Scarpa RC,Huang X,et al.Characterization of copperinter actions with Alzheimer Aβ peptides-Identification of an attomolar affinity copper binding site on Aβ1-42[J].JNeurochem,2000,75:1219-33.
[120]ChernyR A,LeggJT,CLeamCA,et al.Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by bimert aldepletion [J].J BiolChem,1999,274:23223-8.
[121]Cherny RA,Atwood CS,Xilinas M,et al.Treatment with acopper-zinc chelator marked lyandrapidly inhibitsβ-amyloidaccumulationin Alzheimer's disease transgenic mice [J].Neuron,2001,30:665-76.
[122]FassbenderK,Simons M,Bergmann C,et al.Simvastatin strongly reduces levels of Alzheimer's disease amyloid peptides Aβ42 [J].Natl AcadSci,2001,98:5856-61.
[123]MartineA,Alonso M,CastroA,et al.Firstnon-ATP competitive glycogen synthase kinase3β(GSK-3β)inhibitors as potential drugs for the treatment of Alzheimer's disease [J].J Med Chem,2002,45:1292-99.
[124]Cras P.Recent developments in Alzheimer's disease [J].Acta Clin Belg,2001,56(5):269-78.
[125]Glabe C.Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease [J].J Mol Neurosci,2001,17(2):137-45.
[126]Esiri MM.Is an effective immune intervention for Alzheimer's disease in prospect?[J].Trends Pharmacol Sci,2001,22(1):2-3.
[127]Selkoe D J.The origins of Alzheimer disease:a is for amyloid [J].JAMA,2000,283(12):1615-17.
[128]Benl C.Alzheimer's disease and oxidative stress:implications for novel therapeutic approehes[J].Prog Neurobiol,1999,57(3):301-23.
[129]Alvarez XA,Miguel HJ,Femadez NL,et al.Intrahippocampal injections of the beta-amyloid 1-28 fragment induces behavioral deficits in rats [J].Methods Find Exp Clini Pharmacol,1997,19(7):471-9.
[130]Yan SD,Chen X,Fu J,et al.RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease [J].Nature,1996,382(6593):685-91.
[131]Weninger SC,Yankner BA.Inflammation and Alzheimer disease:the good,the bad,and the ugly [J].Nat Med,2001,7(5):527-8.
[132]Blass JP.Immunologic treatment of Alzheimer's disease [J].N Engl J Med.1999,341(22):1694-1705.
[133]Frenkel D,Kariv N,Solomon B.Generation of auto-antibodies towards Alzheimer's disease vaccination [J].Vaccine,2001,19(17-19):2615-19.
[134]Morgan D,Diamond DM,Gottschall PE,et al.A beta peptide vaccination prevents memory loss in an animalmodel of Alzheimer's disease [J].Nature,2000,408(6815):982-5.
[135]Janus C,Pearson J,McLaurin J,et al.A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease [J].Nature,2000,408(6815):979-82.
[136]Lambert MP,Viola KL,Chromy BA,et al.Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies [J].J Neurochemi,2001,79(3):595-605.
[137]DeMattos RB,Bales KR,Cummins DJ,et al.Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease [J].PNAS,2001,98(15):8850-5.
[138]Bard F,Cannon C,Barbour R,et al.Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease [J].Nat Med,2000,6(8):916-9.
[139]Virginia ML.Aβ immunization:moving Aβ peptide from brain to blood [J].PNAS,2001,98(16):8931-2.
[140]Games D,Bard F,Guido T,et al.Prevention and reduction of AD-type pathology in PDAPP mice immunized with A beta 1-42 [J].Ann NY AcADSci,2000,920:274-84.
[141]Alon M,Ruth M,Victor Z,et al.Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice:Implications for the pathogenesis and treatment of Alzheimer's disease [J].PNAS,2001,98(18):10273-8.
[142]Dan F,Odelia K,Beka S,et al.Immunization against Alzheimer's disease β-amyloid plaques via EFRH phage administration [J].PNAS,2000,97(19):11455-9.
[1]Tuppo EE,Arias HR.The role of inflammation in Alzheimet's disease [J].Int J Bioc hem Cell Biol,2005,37(2):289-305.
[2]Gehrmann J.Microglia:a sensor to threats in the nervous system? [J].Res Virol,1996,147(2-3):79-88.
[3]Flugel A,Bradl M,Kreutzberg GW,et al.Transformation of donor-derived bone marrow precursors into host microglia during auto immune CNS inflammation and during the retrograde response to axotomy [J].J Neurosci Res,2001,66(1):74-82.
[4]SimardAR RivestS.Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia [J].FASEB J,2004,18(9):998-1000.
[5]SimardA R,SouletD,Gowing G.et al.Bonemarrow.de.rived microglia play a critical role in restricting senile plaqueformation in Alzheimer's disease [J].Neuron,2006,49(41):489-502.
[6]Vilhardt F.Microglia:phagocyte and glia cell [J].Int J Biochem CeU Biol,2005,37(1):17-21.
[7]Matin-Tleva JL,Dusart I,Colin C,et al.Microglia promote the death of developing Purkinjecells[J].Neuron,2004,41(4):535-47.
[8]Polazzi E,Contestable A.Reciprocal interactions between microgfiaandneurons:from survival to neuropathology [J].Rev Neurosci,2002,13(3):221-42.
[9]Kreutzberg GW.Microglia:a sensor for pathological events in the CNS [J].Trends Neurosci,1996,19(8):312-8.
[10]Raivich G.Banati R.Brain microglia and blood-derived macrophages:molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease [J].Brain Res Brain Res Rev,2004,46(3):261-81.
[11]Haughey NJ,Nath A,Chan SL,et al.Disruption of neurogenesis by amyloid peptide,and perturbed neural progenitor cell homeostasis,in models of Alzheimer's disease [J].J Neurochem,2002,83(6):1509-24.
[12]Jacobs BL.Adult brain neurogenesis and depression [J].Brain Behav Inunun,2002,16(5):602-9.
[13]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34(7-8):491-500.
[14]LiuB.Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases mechanisms and strategies for therapeutic intervention [J].J Pharmacol Exp Ther,2003,304(1):1-7.
[15]Pocock JM.Liddle AC.Microglial signalling cascades in neurodegenerative disease[J].Prog Brain Res,2001,132:555-65.
[16]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke [J].Ernst Schering Res Found Workshop,2002(39):105:32.
[17]Hanisch UK.Microglia as a source and target of cytokines [J].Glia,2002,40(2):140-55
[18]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects [J].Microsc Res Tech,2001,54(1):47-58.
[19]Seabrook TJ,Jiang L,Maier M,et al.Minocycline affects microglia activation,Abeta deposition,and behavior in APP-tg mice [J].Glia,2006,53(7):776-82.
[20]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation [J].Glia,2006,53(3):233-40.
[21]Xia MQ,Qin SX,Wu LJ,et al.Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains [J].Am J Pathol,1998,153(1):31-7.
[22]Xia MQ,Bacskai BJ,Knowles RB,et al.Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes:in vitro ERK1/2 activation and role in Alzheimer's disease [J].J Neuroimmunol,2000,108(1-2):227-35.
[23]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell injury via a nitric oxide mechanism [J].J Immunol,1992,149(8):2736-41.
[24]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease [J].Biochim Biophys Acta,1997,1362(1):77-86.
[25]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons [J].Exp Neurol,2001,169(2):219-30.
[26]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration [J].Ann NY AcADSd,2002,962:318-31.
[27]Frautschy SA,Cole GM,Baird A.Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid [J].Am J Pathol,1992,140(6):1389-99.
[28]Weldon DT,Rogers SD,Ghilardi JR,et al.Fibrillar beta-amyloid induces microglial phagocytosis,expression of inducible nitric oxide synthase,and loss of a select population of neurons in the rat CNS in vivo [J].J Neurosci,1998,18(6):2161-73.
[29]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid beta protein deposition [J].ActaNeuropathol(Bed),1997,94(4):316-22.
[30]Meda L,Cassatella MA,Szendrei G I,et al.Activation of microglial cells by β-amyloid protein and interferon-γ[J].Nature,1995,374(6523):647-50.
[31]Vincent VA,Tilders FJ,Van Dam AM.Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells:a role for transforming growth factor beta [J].Glia,1997,19(3):190-8.
[32]Aloisi F.Immune function of microglia [J].Gila,2001,36(2):165-79.
[33]Weisman D,Hakimian E,Ho GJ.Intefleukins,inflammation,and mechanisms of Alzheimer's disease [J].Vitam Horm.2006,74:505-30.
[34]Tsirka SE.Clinical implications of the involvement of tPA inneuronal cell death [J].J Mol Med,1997,75(7):341-7.
[35]Tan J,TownT,Paris D,et al.Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation [J].Science,1999,286(5448):2352-5.
[36]Aloisi F,Penna G,Polazzi E,et al.CD40-CD154 interaction and IFN-gamma are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells[J].J Immunol.1999.162(3):1384-91.
[37]Lee da Y,Park KW,Jin BK.Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro:proteolytic and non-proteolytic actions [J].Biochem Biophys Res Commun,2006,346(3):727-38.
[38]Choi SH,Lee DY,Kim SU,et al.Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo:role of microglial NADPH oxidase [J].J Neurosci,2005,25(16):4082-90.
[39]Kim YS,Kim SS,Cho JJ,et al.Matrix metalloproteinase-3:a novel signaling proteinase from apoptotic neuronal cells that activates microglia [J].J Neurosci.2005,25(14):3701-11.
[40]Eder C.Ion channels in mi croglia(brain rnacrophages) [J].Am J Physiol,1998,275(2n pt 1):327-42.
[41]Suzumura A,Sawada M,Takayanagi T.Production of intedeukin-12 and expression of its receptors by murine microglia [J].Brain Res,1998,787(1):139-42.
[42]Koo EH,Park L,Selkoe DJ.Amyloid β-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth [J].Proc Natl AcADSci USA,1993,90(10):4748-52.
[43]Behl C.Amyloid β-protein toxicity and oxidative stress in Alzheimer's disease [J].Cell Tissue Res,1997,290(3):471-80.
[44]Cotter RL,Burke WJ,Thomas VS,et al.Insights into the neurodegenerative process of Alzheimer's disease:a role for mononuclear phagocyte-associated inflammation and neurotoxicity [J].J Leukoc Biol,1999,65(4):416-27.
[45]Casal C,Serratosa J,Tusell JM.Effects of beta-AP peptides on activation of the transcription factor NF-kappaB and in cell proliferation in glial cell cultures [J].Neurosci Res,2004,48(3):315-23.
[46]El Khoury J,Hickman SE,Thomas CA,et al.Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils [J].Nature,1996,382(6593):716-9.
[47]Roy A,Fung YK,Liu X,et al.Upregulacion of micmglial CD11b expression bvnitric Oxide [J].J Biol Chem,2006,281(21):14971-80.
[48]Lorton D.beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium-and G-protein-dependent [J].Mech Ageing Dev,1997,94(1-3):199-211.
[49]Combs CK,Johnson DE,Cannady SB,et al.Identifcation of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of β-amyloid and prion proteins [J].J Neurosci,1999,19(3):928-39.
[50]Streit WJ,Sparks DL.Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits [J].J Mol Med,1997,75(2):130-8.
[51]Bartholdi D,Schwab ME.Expression of proinflammatory cytokine mRNA upon experimental spinal cord injury in mouse:an in situ hybridization study [J].Eur J Neurnsie,1997,9(7):1422-38.
[52]Benveniste EN.Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis.[J].J Mol Med,1997,75(3):165-173.
[53]Casal Ct Serratosa J,Tusell JM.Relationship btm n beta AP peptide aggregation and microlial activation [J].Brain Res,2002,928(1-2):76-84.
[54]Taniwaki Y,KatoM,Araki T,et al.Microglial activation by epileptic activities through the propagation pathway of kainic acidinduced hippocampal seizures in the rat [J].Neurosci Lett,1996,217(1):29-32.
[55]Ferrari D,Chiozzi P,Falzoni S,et al.Purinergic modulation of lL1beta release from microglial cells stimulated with bacterial endotoxin [J].J Exp Med,1997,185(3):579-82.
[56]Kakimura J,Kitamura Y,Takata K,et al.Mioroglial activation and amyloid beta clearance induced by exogenous heat-shock proteins [J].FASEB J,2002,16(6):601-3.
[57]Spleiss O,Appol K,Boddeke HW,et al.Molecular biology of microglia cytokine and chemokine receptors and microbial activation [J].Life Sei,1998,62(17-18):1707-10.
[58]Laurenzl MA,Areuri C,Ressi R,et al.Efects of microenvironment on morphology and function of the microglial cell line BV2 [J].Neurnchem Res,2001,26(11):1209-16.
[59]Kettenmann H,Hoppe D,Gottmann K,et al.Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages [J].J Neurosci Res,1990,26(3):278-87.
[60]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial: identification of a proteinase inhibitor that increase microglial cell number [J].Mol Brain Res,1998,56(1-2):99-107.
[61]Hanasaki K,Yokota Y,Ishizaki J.et al.Resistance to endotoxic shock in phospholipase A2 receptor-defieientmice[J].J Biol Chem,1997,272(52):32792-7.
[62]Paris D,Town T,Mullan M.Novel strategies for opposing murine microbial activation [J].Neurosci Lett,2000,278(1-2):5-8.
[63]Sanz O,Acarin L,Gonzalez B,et al.NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain [J].J Neuroaci Res,2002,67(6):772-80.
[64]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extraeellular ATP [J].J Immunol,1996,156(4):1531-9.
[65]Kaltschmidt C,Lannes-Vieira J,Kreutzberg GW,et al.Transcription factor NF-kappa B is activated in microglia during experimental autoimmune encephalomyelitis.[J].J Neuro Immunol,1994,55(1):99-106.
[66]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia [J].J Neuroimmunol,1998,92(1-2):170-8.
[67]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cellines:expression of cytokines and chemokines [J].Neurobiol Dis,2001,8(6):1057-68.
[68]Saha RN,Pahan K.Regulation of inducible nitric oxide synthase gene in glial cells [J].Antioxid Redox Signal,2006,8(5-6):929-47.
[69]Yon Bernhardi R,Eugenin J.Microglial reactivity to β-amyloid is modulated by astrocytes and proinflammatory factors [J].Brain Res,2004,1025(1-2):186-93.
[70]Velez-Pardo C,Ospina GG,Jimenez del Rio M.Abeta[25-35]peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism:involvement of H_2O_2,caspase-3,NF-kappaB,p53 and c-Jun [J].Neurotoxicology,2002,23(3):351-65.
[71]Jang MH,Jung SB,Lee MH,et al.Melatonin attenuates amyloid p25-35-induced apoptosis in mouse microglial BV2 cells [J].Neurosci Lett,2005,380(1-2):26-31.
[72]Nakamura S,Kawamata T,Akiguchi I,et al.Reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry in neocortex and hippocampus in patients with Alzheimer type dementia and aged controls [J].Rinsho Shinkeigaku,1987,27(8):1059-63.
[73]Wilkinson BL,Landreth GE.The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease [J].J Neuro inflammation,2006,3:30.
[74]Adams JD Jr,Klaidman LK,Chang ML,et al.Brain oxidative stress--analytical chemistry and thermodynamics of glutathione and NADPH [J].Curr Top Med Chem,2001, 1(6):473-82.
[75]Qin B,Carrier L,Dubois-Dauphin M,et al.A key role for the microglial NADPH oxidase in APP-dependent killing of neurons [J].Neurobiol Aging,2006,27(11):1577-87
[76]Jekabsone A,Mander PK,Tickler A,et al.Fibrillar beta-amyloid peptide Abeta 1-40 activates microglial proliferation via stimulating TNF-alpha release and H202 derived from NADPH oxidase:a cell culture study [J].J Neuroinflammation,2006,3:24.
[77]Lue LF,Walker DG,Brachova L,et al.Involvement of microgtial receptor for advanced glycation endproducts(RAGE)in Alzheimer's disease:identification of a cellular activation mechanism [J].Exp Neurol,2001,171(1):29-45.
[78]Liu Y,Qin L,Wilson BC,et al.Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons [J].J Pharmacol Exp Ther,2002,302(3):1212-19.
[79]CoraciI S,Husemann J,Berman JW,et al.CD3 6 a class B scavenger receptor,is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils [J].Am J Pathol,2002,160(1):101-12.
[80]Walker DG,Lue LF,Beach TG.Gene expression profiling of amyloid p peptide-stimulated human post-mortem brain microglia [J].Neurobiol Aging,2001,22:957-66
[81]Akiyama H.Abeta,tau and alpha-synuclein and glial cells [J].Nihon Shinkei Seishin Yakurigaku Zasshi,2006,26(1):23-31.
[82]Kitazawa M,Yamasak TR,LaFerla FM.Microglia as a potential bridge between the amyloid β-peptide and tau [J].Ann NY AcADSci,2004,1035:85-103.
[83]Uchihara T,Duyckaerts C,Seilhean D,et al.Exclusive induction of tau2 epitope in microglia/macrophages in inflammatory lesions-tautwopathy distinct from degenerative tauopathies[J].Acta Neuropathol(Bed),2005,109(2):159-64.
[84]Quintanilla RA,Orellana DI,Gonzalez-Billault C,et al.Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway.Exp Cell Res.2004.295(1):245-57.
[85]Li Y,Liu L,Barger SW,et al.Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway.J Neurosci.2003,23(5):1605-11.
[86]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation [J].Neurochem Int.2001,39(5-6):341-8.
[87]Kitazawa M,Oddo S,Yam asaki TR,et al.Lipopolysaccha ride-induced inflamm ation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a tran sgenic model of Alzheimer's disease [J].JNeurosci.2005.25(39):8843-53.
[88]Griffin WS,Sheng JG,Roberts GW,et al.Interleukin-1 expression in diferent plaque types in Alzheimer's disease:significance in plaque evolution [J].J Neuropathol Exp Neurol,1995,54(2):276-81.
[89]Apelt J,Schliebs R.β-amyloid-induced glial expression of both pro-and anti inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology [J].Brain Res.2001,894(1):21-30.
[90]Bellucci A,Westwood AJ,Ingram E,et al.Induction of inflammatory mediators and microglial activation in mice transgenic formutant human P301S tau protein [J].AmJPathol,2004,165(5):1643-52.
[91]Holmlund L,Cortes Toro V,Iverfeldt K.Additive effects of amyloid β fragment and interleukin 1β on interleukin 6 secretion in rat primary glial cultures [J].Int J Mol Med,2002,10(3):245-50.
[92]NessaBN,TanakaT,Kamino K,etal.Toll like receptor 3 mediated hyper phosphorylation of tau in human SH-SY5Y neuroblastoma cells [J].Psychiatry Clin Neurosci.2006,60 Suppl 1:S27-33.
[93]Casal C,Serratosa J,Tusell JM.Relationship between beta-AP peptide aggregation and microglial activation [J].Brain Res.2002,928(1-2):76-84.
[94]Takata K,Kitamura Y,Umeki M,et al.Possible involvement of small oligomers of amyloid-beta peptides in 15-deoxy-delta 12,14 prostaglandin J2-sensitive microglial activation [J].J Pharmacol Sci.2003,91(4):330-3.
[95]Hashioka S,MonjiA,Ueda T,et al.Amyloid-beta fibril formation is not necessarily required for microglial activation by the peptides [J].Neurochem Int.2005,47(5):369-76.
[96]Sebastiani G,Morissette C,Lagac(?) C,et al.The cAMP-specific phosphodiesterase 4B mediates Abeta-induced microglial activation [J].Neurobiol Aging.2006,27(5):691-701.
[97]Wilcock DM,Di Carlo G,Henderson D,et al.Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation [J].J Neurosci,2003,23(9):3745-51.
[98]Koenigsknecht J,Landreth G Microglial phagocytosis of fibrillar beta-amyloid through a betal integrin-dependent mechanism [J].J Neurosci.2004,24(44):9838-46.
[99]Von Bernhardi R,Ramirez G,Toro R,et al.Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture [J].Neurobiol Dis.2007,26(1):153-64.
[100]Takata K,Kitamura Y,Yanagisawa D,et al.Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats [J].FEBS Lett.2007,581(3):475-8.
[2]Han DW.Intestinal endotoxemia as a pathogenetic mechanism in liver failure(Topic Comment)[J].World J Gaotroenteral,2002,8(6):961-5.
[3]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[4]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细胞化学研究[J].西安医科大学学报(中文版),1997,18(3):304-7.
[5]White DM,Longstreth WT Jr,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[6]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) in mice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[7]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration ofdeferoxamine[J].Behav Neurosci,1989,103:779.
[8]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[9]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-5.
[10]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-8.
[11]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[12]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-2.
[13]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(中国药理学报),2001,22(12):1078-83.
[14]Goto T,Eden S,Nordenstam G,et al.Endotoxin levels in sera of elderly individuals[J].Clin Diagn Lab Immunol,1994,1(6):684-8.
[15]黎君友,于燕,郝军,等.分光光发法测定血和小肠组织二胺氧化酶活性[J].氨基酸和生物资源,1996,18(4):28-30.
[16]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[17]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[18]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].Prog BrainRes,2001,132:555-65.
[19]Pocock JM,Liddle AC,Hooper C,etal.Activated microglia in Alzheimer' s disease and stroke[J].Ernst Schering Res Found Workshop,2002(39):105-32.
[20]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[21]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[22]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell iniury via anitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[23]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson' s disease[J].Biochim Biophys Acta,1997,1362:77-86.
[24]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[25]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation- mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[26]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[27]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation andhuman microglial activation[J].Glia,2006,53:233-40.
[28]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[29]Hanasaki K,Yokota Y,Ishizaki J.et al.Resistance to endotoxic shock in phospholipase A2 reeeptor defieient mice[J].J Biol Chem,1997,272:32792-7.
[30]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extraeellular ATP[J].J Immunol,1996,156:1531-9.
[31]Kaltschmidt CB,Lallnes Vieiva J,Kreutzberg Gw,et al.Transcription factor NF-κB is activated in microglial during experimental autoimmune encephalomyelitis [J].J Neuro Immunol,1994,55:99-106.
[32]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia [J].J Neuroimmunol,1998,92(1-2):170-8.
[33]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cel lines:expression of cytokines and chemokines [J].Neurobiol Dis,2001,8(6):1057-68.
[34]Kawahara M,Kuroda Y.Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein:channel formation and disruption of calcium homeostasis [J].Brain Res Bull,2000,53(4):389-97.
[35]Suh YH.An etiological role of amyloidogenic carboxy-terminat fragments of the beta-amyloid precursor protein in Alzheimer's disease [J].J Neurochem,1997,68;1781-91.
[36]Weiss JH,Pike CJ,Cotman CW,et al.Ca channel blockers attenuate amyloid peptides toxicity to cortical neurons in culture [J].J Neurochem,1994,62:372-375.
[37]Ingram VM.The role of Alzheimer A beta peptides in ion transport across cell membranes [J].Subcell Biochem,2005,38:339-49.
[38]Ca C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chroinc application of beta-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203:61-65.
[39]Guo Q,Robinson N,Mattson M.Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant prusenilin-1 by activation of NF-kappa B and stabilization of calcium homeostasis [J].J Biol Chem,1998,273:12341-51.
[1]Small GW,Rabins PV,Barry PP,et al.Diagnosis and treatment of Alzheimer disease and related disorders.Consensus statement of the American Association for Geriatric Psychiatry,the Alzheimer's Association,and the American Geriatrics Society[J].JAMA,1997,278(16):1363-71.
[2]Labo LJ,Launer LJ,Fratiglioni L,et al.Prevalence of dementia and major subtypes in Europe:A collaborative study of population basedcohorts[J].Neurology,2000,54(suppl5):s4-s9.
[3]邹开利,漆静,何源,等.重庆渝中区街道老年期痴呆横断面研究[J].中华老年医学杂志,2002,21(6):433-6.
[4]屈秋民,乔晋,扬剑波,等.西安地区中老年人的痴呆患病率调查[J].中华老年医学杂志,2001,20(4):283-6.
[5]张振馨,魏镜,洪霞,等.北京城乡痴呆及其主要亚型的患病率[J].中华神经科杂志,2001,34(5):199-203.
[6]周玢,洪震,黄茂盛.上海城市人群痴呆患病率调查[J].中华流行病学杂志,2001, 22(5):368-72.
[7]唐牟尼,刘协和,邹晓毅,等.成都地区老年期痴呆患病率调查[J].中华精神科杂志,2001,34(4):226-30.
[8]余金龙,冯容妹,方小心,等.广东省沿海地区农村老年期痴呆的患病率调查[J].中国神经精神杂志,1998,24(1):30-2.
[9]Kchin HFK,Lain LCW,Chi I,et al.Prevelence of dementia in Chinese elderly in Hong Kong[J].Neurology,1998,50:1002-9.
[10]吕书臣,余海民,陈勇华,等.舟山市定海城区老年痴呆流行病学调查[J].中华精神科杂志,1998,31(4):225-7.
[11]高至胜,盛小奇,单飞豹,等.湖南省长沙市老年期痴呆流行病学调查[J].湖南医学,1994,11(4):195-6.
[12]唐牟尼,郭杨波,向孟泽,等.农村老年期痴呆和Alzheimer病流行病学调查报告[J].临床精神医学杂志,1999,9(1):20-2.
[13]王天祥,孙建中,韦学斌,等.安徽某地区、农村老年性痴呆流行病学调查[J].职业与健康,1999,15(11):43-5.
[14]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neual,1999,56(9):1121-3.
[15]胡昔权,钱采韵,窦祖林,等.Alzheimer病与老年脑中β淀粉样蛋白免疫组化的研究[J].中国神经精神疾病杂志,1998,24(1):6.
[16]Mcquade R,Young A H.Future therapeutic targets in mood disorders:the glucocorticoid receptor[J].Br J Psychiatry,2000,177(2):390-5.
[17]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[18]李权益,高薮幔.分子医学--艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-180.
[19]Weller R O,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:110-7.
[20]陈明,李爱媛.Alzheimer病与神经元钙稳态[J].生命的化学,1997,17(3):46-9.
[21]Rogers J,Webster S,Lue LF,et al.Inflammation and Alzheimer's disease pathogenesis [J].NeurobiolAging,1996,17(5):681-6.
[22]Blasko I,Veerhuis R,Stampfer-Kountchev M,et al.Costimulatory effects of interferongamma and interleukin-1 beta or rumor necrosis factor alpha on the synthesis of A betal-40 and A betal-42 by human asteocytes[J].Neurobiol Dis,2000,7(6 Pt B):682-9.
[23]Lukiw WJ,Bazan NG.Neuroinflammatory signaling upregulation in Alzheimer's disease[J].Neurochem Res,2000,25(9210):1173-84;
[24]Mattson MP.Apoptosis in neurodegenerative disorders[J].Nat Pev Mol Cell Biol,2000,1(2):120-9.
[25]Tan J,Town T,Mori T,et al.CD45 opposes beta amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase[J].Neurosci,2000,20(20):7587-94.
[26]Combs CK,Karlo JC,Kao SC,et al.beta Amyloid stimulation of microglia and monocytes results in TNF alpha-dependant expression of inducible nitric oxide synthase and neuronal apoptosis[J].Neurosci,2001,21(4):1179-88.
[27]Brahimi F,Bertrand P,Starck M,et al.Control of apolipoprotein E secretion in the human hepatoma cell line KYN22[J].Cell Biochem Funct,2001,19(1):51-8.
[28]Gitter BD,Boggs LN,May PC,et al.Regulation of cytokine secretion and amyloid precursor protein processing by proinflammatory amyloid Peta(A beta)[J].Ann N Y AcADSci,2000,917:154-64.
[29]Cagnin A,Brooks DJ,Kennedy AM,et al.Invivo measurement of activated microglia in dementia[J].Lancet,2001,358(9280):461-7.
[30]Dandrea MR,Reiser PA,Gumula NA,et al.Application of triple immuno-histochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer's disease[J].Biotech Histochem,2001,76(2):97-106.
[31]Giulian D,Haverkamp LJ,Yu JH,et al.Specific domains of beta-amyloid from Alzheimer's plaque elicit neuron killing in human microglia[J].J Neurosci,1996,16(19):6021-37
[32]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo[J].Exp Neurol,2000,163(2):388-91.
[33]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation[J].Neurochem Int,2001,39(526):341-8.
[34]Grammas P,Ovase R.Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain[J].Am J Pathol,2002,160(5):1583-7.
[35]Hoozemans J,Veerhuis R,Janssen I,et al.The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia:implications for Alzheimer's disease[J].Brain Res,2002,951(2):218-26.
[36]O'Banion MK,Miller JC,Chang JW,et al.Interleukin-1 beta induces prostaglandin G/H synthase-2(cyclooxygenase-2) in primary murineastrocyte cultures[J].J Neuro chem,1996,66(6):2532-40.
[37]Ho L,Pieroni C,Winger D,et al.Regionaldistribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease[J].J Neurosci Res,1999,57(3):295-303.
[38]Xiang Z,Ho L,Yemul S,et al.Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology[J].Gene Expr,2002,10(526):271-8.
[39]Webster SD,Yang AJ,Margol L,et al.Complement component C1q modulates the phagocytosis of A beta by microglia[J].Exp Neurol,2000,161(1):127-38.
[40]Shen Y,Lue L,Yang L,et al.Complement activation by neurofibrillary tangles in Alzheimer's disease[J].Neurosci Lett,2001,305(3):165-8.
[41]Bradt BM,Kolb WP,Cooper NR.Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide[J].J Exp Med,1998,188(3):431-8.
[42]McGeer EG,Yasojima K,Schwab C,et al.The pentraxins possible role in Alzheimer's disease and other innate inflammatory disease[J].Neurobiol Aging,2001,22(6):843-8.
[43]McGeer PL,Walker DG,Pitas RE,et al.Apolipoprotein E4(ApoE4) but not ApoE3 or ApoE2 potentiates beta-amyloid protein activation of complement in vitro[J].Brain Res,1997,749(1):135-8.
[44]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:110-7.
[45]韩德五,肝功能衰竭发病机制的研究-肠源性内毒素血症假说[J].中华肝脏病杂志,1995,3(3):134-7
[46]Han DW.Intestinal endotoxemia as a pathogenetic mechanism in liver failure(Topic Comment)[J].World J Gaotroenteral,2002,8(6):961-5.
[47]Goto T,Eden S,Nordenstam G,et al.Endotoxin levels in sera of elderly individuals[J].Clin Diagn Lab Immunol,1994,1(6):684-8.
[48]Wilmore DW,Smith RJ,O'Dwyer ST,et al.The gut:A central organ after surgical stress[J].Sugery,1988,104:917-23.
[49]Marshall J,Sweeney D.Microbial Infection and the septic response in critical surgical [J].Arch Surg,1990,125:17-23.
[50]徐鹏远,蒋朱明,孙永华,等.手术/创伤后外周血内毒素研究[J].中华实验外科,1999,16:298-9.
[51]Faries PL,Simon RJ,Martella AT,et al.Intestinal permeability correlates with severity of injury in trauma patients[J].J Trauma,1998,44:1031-6.
[52]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[53]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细 胞化学研究.西安医科大学学报(中文版),1997,18(3):304-7.
[54]White DM,Longstreth WT Jr,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[55]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) inmice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[56]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration of deferoxamine[J].Behav Neurosci,1989,103:779.
[57]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[58]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-5.
[59]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-8.
[60]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[61]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-2.
[62]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(中国药理学报),2001,22(12):1078-83.
[63]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[64]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[65]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].Prog Brain Res,2001,132:555-65.
[66]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke[J].Ernst Schering Res Found Workshop,2002(39):105-32.
[67]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[68]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[69]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[70]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation and human microglial activation[J].Glia,2006,53:233-40.
[71]Chao CC,Hu S,MolitorTW,et al.Activated microglia mediate neuronal cell iniury via a nitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[72]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease[J].Biochim Biophys Acta,1997,1362:77-86.
[73]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[74]Liu B,Gao HM,W ang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[75]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[76]Hanasaki K,Yokota Y,Ishizaki J,et al.Resistance to endotoxic shock in phospholipase A2 receptor deficient mice[J].J Biol Chem,1997,272:32792-7.
[77]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extracellular ATP[J].J Immunol,1996,156:1531-9.
[78]Kaltschmidt CB,Lallnes Vieiva J,Kreutzberg Gw,et al.Transcription factor NF KB is activated in microglial during experimental autoimmune encephalomyelitis[J].J Neuro Immunol,1994,55:99-106.
[79]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia[J].J Neuroimmunol,1998,92(1-2):170-8.
[80]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cel lines:expression of cytokines and chemokines[J].Neurobiol Dis,2001,8(6):1057-68.
[1]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004:18(1):22-26.
[2]郭贵文,吴亚兰,杨小红等.氯化铝对大鼠脑组织胶质原酸性纤维蛋白和淀粉样β-蛋白前体基因表达的影响[J].中国药理学与毒理学杂志,1999,13(3):227-30.
[3]钱亦华;杨杰;任惠民,等.痴呆模型大鼠背海马结构内淀粉样蛋白沉积的免疫细胞化学研究[J].西安医科大学学报(中文版),1997,18(3):304-7.
[4]White DM,Longstreth WT JR,Rosenstock L,et al.Neurologic syndrome in 25 workers from an aluminum smelting planet[J].Arch Intern Med,1992,152:1443-8.
[5]Yen-koo HC.The effect of aluminum on conditioned avoidance(CAR) inmice[J].Toxicol Ind Health,1992,8(1-2):1-7.
[6]Connor DJ,Harrell LE,Jope KS.Revesal of an aluminum induced behav-ioral deficit by administration of deferoxamine[J].Behav Neurosci,1989,103:779.
[7]龚国清,徐黼本.小鼠衰老模型研究[J].中国药物大学学报,1991,22:101-3.
[8]李文彬,韦丰,范明,等.D-半乳糖在小鼠上诱导的拟脑老化效应[J].中国药理学与毒理学杂志,1995,9:93-95.
[9]田苏平,张小虎,李军,等.游泳应激不同时间对衰老小鼠学习记忆及脑内脂褐素含量的影响[J].实用老年医学(抗衰老特集),1997,11:56-58.
[10]钱小明,吴振国,施志明,等.衰老小鼠组织牛磺酸含量与脂质过氧化损伤的关系[J].基础医学与临床,1995,15:390.
[11]任榕娜,陈新民.避暗记迷宫实验研究锌缺乏及锌过量对大鼠学习记忆的影响[J].现代预防医学,1997,24(1):61-62.
[12]Shang YZ,Gong MY,Zhou XX,et al.Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J].Acta Pharmacol Sin(可路药理学报),2001,22(12):1078-83.
[1]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann NY Acad Sci,2000,903:110-7.
[2]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[3]李权益,高薮幔.分子医学--艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-180.
[4]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neural,1999,56(9):1121-3.
[5]吴江,张昱.无名质区破坏的wistar大鼠脑内胆碱乙酰转移酶和生长抑素活性的变化及相互关系[J].中风与神经疾病杂志,1995,3:911.
[6]Salvaterra PM.Molecular biology and neurobiology of choline acetyltransferase[J].Mol Neurobiol,1987,1(3):247.
[7]Markesbery WR.Oxidative stress hypothesis in Alzheimer's disease[J].Free Radic Biol Med,1997,23(1):134-47.
[8]O'Mahony S,Harkany T,Rensink AA,et al.Beta amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex:reversal by NMDA receptor blockade[J].BrainRes,1998,45(4):405-11.
[9]Wevers A,Monteggia L,Nowacki S,et al.Expression of nicotinic acetyl choline receptor subunits in the cerebralcortex in Alzheimer's disease:histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein[J].J Eur Neurosci,1999,11(7):2551-65.
[10]Law A,Gauthier S,Quirion R.Say NO to Alzheimer's disease:the putative links between nitric oxide,and dementia of the Alzheimer's type[J].Brain Res Rev,2001,35:73-96.
[11]Meyer RC,Spangler EL,Kametani H,et al.Ageassociated memory impairment:Assessing the role of nitric oxide[J].Ann NY Acad Sci,1998,854:307-17.
[12]Pluta R,Misicka A,Nidan RU,et al.Transport of human beta-amyloid peptide through the rat blood brain barrier after global cerebral is chemia[J].Acta Neurochir,1997,70(suppl):247-9.
[1]Hockenbery D.Defining apoptosis[J].Am J Pathol,1995,146(1):16-9.
[2]Lassmann H,Bancher C,Breitschopf H,et al.Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ[J].Acta Neuropathol,1995,89(1):35-41.
[3]Su JH,Anderson AJ,Cummings BJ,et al.Immunohistochemical evidence for apoptosis in Alzheimer's disease[J].Neuroreport,1994,5:2529-33.
[1]Glenner G G,Wong C W.Alzheimer's disease:initial report of the purification and characterization of a novel cerebro vascular amyloid protein[J].Biochem Biophys Res Commun,1984,120(3):885-90.
[2]Hardy J A,Higgins G A.Alzheimer's disease:the amyloidcascade hypothesis[J].Science,1992,256(5054):184-5.
[3]Yankner B A,Dawes L R,Fisher S,et al.Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease[J].Science,1989,245(4916):417-20.
[4]Frautschy S A,Baird A,Cole G M.Effects of injected Alzheimer β-amyloid cores in rat brain[J].Proc Natl AcADSci USA,1991,88(19):8362-6.
[5]Pike C J,Walencewicz A J,Glabe C G,et al.In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity[J].Brain Res,1991,563(1-2):311-4.
[6]Lesne S,Koh M T,Kotilinek L,et al.A specific amyloid-b protein assembly in the brain impairs memory[J].Nature,2006,440(7082):352-7.
[7]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid p protein deposition[J].ActaNeuropathol(Bed),1997,94:316-22.
[8]Koo EH,Park L,Selkoe DJ.Amyloid P-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth[J].Proc Natl AcADSci USA,1993,90:4748-52.
[9]Behl C.Amyloid P-protein toxicity and oxidative stress in Alzheimer's disease[J].Cell Tissue Res,1997,290:471-80.
[10]Cotter RL,Burke WJ,Thomas VS,et al.Insights into the neurodegenerative process of Alzheimer's disease:a role for mononuclear phagocyte-associated inflammation and neurotoxicity[J].J Leukoc Biol,1999,65:416-27.
[11]Casal C,Serratosa J,Tusell JM.Effects of P-AP peptides on activation of the transcription factor NF-κB and in cell proliferation in glial cell cultures[J].Neurosci Res,2004,48:315-23.
[12]E1 Khoury J,Hickman SE,Thomas CA,et al.Scavenger receptor-mediated adhesion ofmicmglia to β-amyloid fibrils[J].Nature,1996,382:716-9.
[13]Roy A,Fung YK,Liu X,et al.Up-regulacion of microglial CD 11b expression by nitric oxide[J].J Biol Chem,2006,281:14971-80.
[14]Lorton D.β-Amyloid-induced IL-1β release from an activated human monocyte cell line is calcium-and G-protein-dependent[J].Mech Ageing Dev,1997,94:199-211.
[15]Combs CK,Johnson DE,Cannady SB,et al.Identifcation of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of β-amyloid and prion proteins[J].J Neurosci,1999,19:928-39.
[16]Verdier Y,Zarandi M,Penke B.Amyloid b-peptide interactions with neuronal and glial cell plasma membrane:binding sites and implications for Alzheimer's disease[J].J Pept Sci,2004,10(5):229-48.
[17]Kim H S,Lee J H,Lee J P,et al.Amyloid b peptide induces cytochrome C release from isolated mitochondria[J].Neuroreport,2002,13(15):1989-93.
[18]Probst A,Langui D,Ulrich J.Alzheimer's disease:a description of the structural lesions[J].BrainPathol,1991,1(4):229-239.
[19]Meda L,Bernasconi S,Bonaiuto C,et al.P-amyloid(25-35) peptide and IFN-g synergistically induce the production of the chemotactic cytokine MCP-l/JE in monocytes and microglial cells[J].J Immunol,1996,157(3):1213-8.
[20]Mark R J,Hensley K,Butterfield DA,et al.Amyloid b-peptide impairs ionmotive ATPase activities:evidence for a role in loss of neuronal Ca~(2+) homeostasis and cell death[J].J Neurosci,1995,15(9):6239-49.
[21]Davidson RM,Shajenko L,Donta TS.Amyloid P-peptide(AP P) potentiates a nimodipine-sensitive L-type barium conductance in NlE-115 neuroblastoma cells[J].Brain Res,1994,643(1-2):324-7.
[22]Mattson MP,Cheng B,Davis D,et al.P-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity[J].J Neurosci,1992,12(2):376-89.
[23]Behl C,Davis J B,Lesley R,et al.Hydrogen peroxide mediates amyloid β protein toxicity[J].Cell,1994,77(6):817-27.
[24]Butterfield D A,Hensley K,Harris M,et al.b-Amyloid peptide free radical fragments initiate synaptosomal Hpoperoxidation in a sequence-specificfashion:implications to Alzheimer's disease[J].Biochem Biophys Res Commun,1994,200(2):710-5.
[25]Cafe C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chronic application of β-amyloid fragment 25-35 in cortical cultures[J].Neurosci Lett,1996,203(1):61-5.
[26]Mattson M P.Pathways towards and away from Alzheimer's disease[J].Nature,2004,430(7000):631-9.
[27]Casley CS,Land JM,Sharpe MA,et al.P-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons[J].Neurobiol Dis,2002,10(3):258-67.
[28]Blass J P.Brain metabolism and brain disease:is metabolic deficiency the proximatecause of Alzheimer dementia?[J].J Neurosci Res,2001,66(5):851-6.
[29]Takashima A,Honda T,YasutakeK,et al.Activation of tau protein kinase I/glycogen synthase kinase-3b by amyloid βeta peptide(25-35) enhances phosphorylation of tau in hippocampal neurons[J].Neurosci Res,1998,31(4):317-23.
[30]Gotz J,Chen F,van Dorpe J,et al.Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Ap 42 fibrils[J].Science,2001,293(5534):1491-5.
[31]Ferrari A,Hoerndli F,Baechi T,et al.P-Amyloid induces paired helicalfilament-like tau filaments in tissue culture[J].J Biol Chem,2003,278(41):40162-8.
[32]Olney J W,Wozniak D F,Farber N B.Excitotoxic neurodegeneration in Alzheimer disease.New hypothesis and new therapeutic strategies[J].Arch Neurol,1997,54(10):1234-40.
[1]张志灯,曹治云,郑腾,等.改良的大鼠脑组织总RNA抽提方法[J].生物技术通讯,2006,17(5):760-1.
[2]Kang J,Lemaire H G,Unterbeck A,et al.The precursor of Alzheimer's disease amyloid Aβ protein resembles a cellsurface receptor[J].Nature,1987,325(6106):733-6.
[3]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004:18(1):22-26.
[4]韩柏,唐荣华,王锋,等.丹参大黄合剂对拟老年痴呆大鼠学习记忆能力及海马β淀粉样前体蛋白(APP)、早老素1(PS1)表达的影响[J].中华临床医师杂志,2008,2(8):912-7.
[1]Wengarten M.D,Lockwood A H,HWO S Y,et al.A protein factor essential for microtubule assembly[J].Proc Natl AcADSci USA,1975,72:1858-62.
[2]Grundke-Qbali,QBAL K,QUINLAN M,et al.Microtubule associated protein tau.a component of alzheimer paired helical filaments[J].J Biol Chem,1986,261:6084-9.
[3]Cleveland DW,Hwo SY,Kirschner MW.Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly[J].J Mol Bio,1977,116(2):227-47.
[4]Arrasate M,Perez M,Avila J.Tau dephosphorylation at tau-1 site correlates with It ' s association to cell membrane[J].Neurochem Res,2000,25(1):43-50.
[5]Avila J,Lucas JJ,Perez M,et al.Role of tau protein in both physiological and pathological conditions[J].Physiol Rev,2004,84(2):361-84.
[6]Thomas F,Jochen E,Roland B.Tau-mediated cytotoxicity in a pseudohyper-phosphorylation model of Alzheimer's Disease[J].J Neuroscience,2002,22(22):9733-41.
[1]Jeohn GH,Cooper CL,Wilson B,et al.P38 MAPkinase is involved in Lipopoly-saccharide -induced dopaminergic neuronal cell death in rat mesencephalic neuron-glia cultures [J].Anil.N.Y.Acad.Sci,2002,962:332-46.
[2]Flad HD,Loppnow H,Rietschel ET,et al.Agonists and antagonists for lipopoly-saccharide -induced cytokines[J].Immunobiology,1993,187(3-5):303-16.
[3]Grau GE,Frei K,Piguet PF,et al.Interleukin 6 production in experimental cerebral malaria:modulation by anticytokine antibodies and possible role in hypergammaglobulinemia[J].Exp Med,1990,172(5):1505-8.
[4]Heinzel FP.The role of IFN-gamma in the pathology of experimental endotoxemia[J].Immunol,1990,145(9):2920-4.
[5]Heinrich PC,Castell JV,Andus T.Interleukin-6 and the acute phase response[J].Biochem,1990,265(3):621-36.
[6]Mackenzie IR.Anti-inflammatory drugs and Alzheimer-type pathology in aging[J].Neurology,2000,54(3):732-4.
[7]Sheng JG,Mrak RE,Rovnaghi CR,et al.Human brain S100 beta and S100 beta mRNA expression increases with age:Pathogenic implications for Alzheimers disease[J].Neurobiol Aging,1996,17(3):359-63.
[8]Li Y,Liu L,Kang J,et al.Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression[J].J Neurosci,2000,20(1):149-55.
[9]Arvin B,Neville LF,Barone FC,et al.Brain injury and inflammation:a putative role of TNF alpha[J].Ann NY Acad So,1995;765:62-71.
[10]Benvenlste EN.Inflammatory cytokines within the central nervous system:sources,function,and mechanism of action[J].Am J Physiol,1992;263:11-16.
[11]Tarkowski E,Blennow K,Wallin A,et al.Intracerebral production of tumor necrosis factor-alpha,a local neuro protective agent,in Alzheimer disease and vascular dementia[J].J Clin Immunol,1999,19(4):223-30.
[12]Opal SM,Wherry JC,Grint P.Interleukin-10:potential benefits and possible risks in clinical infectious diseases[J].Clinical infectious diseases,1998,27(6):1497-507.
[13]Pajkrt D,Camoglio L,Tiel-van Buul MC,et al.Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia:effect of timing of recombinant human IL-10 administration[J].J Immunol,1997,158(8):3971-7.
[14]VanderPoll T,Jansen PM,Montegut WJ,et al.Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia[J].J Immunol,1997,158(4):1971-5.
[15]Hess PJ,Seeger JM,Huber TS,et al.Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factor-dependent murine model of acute visceral ischemia[J].J Vasc Surg,1997,26(1):113-8.
[16]Engles RE,Huber TS,Zander DS,et al.Exogenous human recombinant interleukin-10 attenuates hindlimb ischemia-reperfusion injury[J]J Surg Res,1997,69(2):425-8.
[17]Aste-Amezaga M,Ma X,Sartori A.et al.Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10[J].J Immunol,1998,160(12):5936-44.
[18]Brown CY,Lagnado CA,Vadas MA,et al.Differential regulation of the stability of cytokine mRNAs in Hpopolysaccharide-activated blood monocytes in response to interleukin-10[J].J Biol Chem,1996,271(33):20108-12.
[1]韩德五.肝脏病理生理学[M].太原:山西高校联合出版社,1992,136.
[2]Richman LK,Klingenstein R J,Richman JA,et al.The murine Kupffer cell.I.Characterization of the cell serving accessory function in antigen-specific T cell proliferation[J].J Immunol,1979,123(6):2602-9.
[3]Murray-Lyon IM,Davidson AR,Rake MO,et al.Hepatic scintiscanning in fulminant hepatic failure[J].Br J Radiol,1973,46(541):30-3.
[4]Naito M,Hasegawa G,Takahashi K.Development,differentiation and maturation of Kupffer cells[J].Microsc Res Tech,1997,39(4):350-64.
[5]Takezawa R,Watanabe Y,Akaike T.Direct evidence of macrophage differentiation from bone marrow cells in the liver:a possible origin of Kupffer cells[J].J Biochem Tokyo,1995,118(6):1175-83.
[6]Decker K.The response of liver macrophages to inflammatory stimulation[J].Keio J Med,1998,47(1):1-9.
[7]Reynolds JV,Murchan P,Redmond HP,et al.Failure of macrophage activation in experimental obstructive jaundice:association with bacterial translocation[J].Br J Surg,1995,82:534-38.
[8]Su L.Lipopolysaccharides in liver injury:molecular mechanisms of Kupffer cell activation[J].Am J Physiol Gastrointest Liver Physiol,2002,283(2):G256-65.
[9]Mochida S,Ohta Y,Ogata I.Fujiwara K.Gut-derived substances in activation of hepatic macrophages after partial hepatectomy in rats[J].J Hepatol,1992,16(3):266-72.
[1]黎君友,于燕,郝军,等.分光光发法测定血和小肠组织二胺氧化酶活性[J].氨 基酸和生物资源,1996,18(4):28-30.
[2]Saadia R,Schein M,MacFarlane C,et al.Gut barrier function and the surgeon[J].Br J Surg,1990,77:487-92
[3]韩德五.肠源性内毒素血症与肝病--肝衰竭的IETM学说.北京:中国科学技术出版社.2004,78-89.
[4]Navaratnam RL,Morris SE,Traber DL,et al.Endotoxin(LPS)increases mesenteric vascular resistance(MVR) and bacterial translocation(BT)[J].J Trauma,1990,30:1104-15.
[5]李晓芳.严重烧伤后胃肠道功能障碍的机制和防治[J].世界华人消化杂志,2006,14:888-93.
[6]Zhang H,Li Y,Wang S,et al.LPS-induced NF-kappa B activation requires Ca~(2+) as a mediator in isolated pancreatic acinar cells of rat[J].Chin Med J(Engl),2003,116:1662-7.
[7]Roland CR,Coss JA,Mangino MJ,et al.Autoregulation by eicosanoids of human Kupffer cell secretory products[J].Ann Sueg,1994,219:389-99.
[8]Chakravortty D,Kumark SN.Modulation of barrier function of small intestinal epithelial cells by lamina propria fibroblasts in response to lipopolysaccharide:Possible role in TNF-α in inducing barrier dysfunction[J].Microbiol Immunol,1999,43(6):527-33.
[9]Souba WW,Herskowitz K,Klimberg VS,et al.The effects of sepsis and endotoxemia on gut gultamine metabolism[J].Ann Surg,1990,211:543-51.
[10]Dudricr PS,Salloum RM,Copeland EM,et al.The early response of jejounal brush border glutamine transporter to endotoxemia[J].J Surg Res,1992,52:372-7.
[11]Koshi R,David S,Mathan Ⅵ,et al.Enteric vascular endothelial response to bacterial endotoxin[J].Int J Exp Path,1993,74:539-601.
[12]Libemaann TA,Baltimore D.Activation of interleukin-6 gene expression through the NF-KB transcription factor[J].Mol Cell Biol,1990,10(5):2327-34.
[13]余佩武,肖光夏,府伟灵,等.血小板活化因子在烧伤大鼠早期肠源性内毒素血症发病中的作用[J].中华医学杂志,1999,79(2):136-8.
[1]王琦,任东青,邝芳,等.脉冲式电磁辐射对大鼠血脑屏障影响的量效关系[J].疾病控制杂志.2003,7(5):401-4.
[2]Gonzalez-Nhriscal L,BetanzosA,lava P,etal.Tightjunctionproteins[J].Progress in Biophysics & Molecular Biology,2003,81:41-44.
[3]Lapierre LA.The molecular structure of the tightjunction[J].Advanced Drag Delivery Reviews,2000,41:255-64.
[4]Nusrat A,Parkos CA,Verkade P,et al.Tight junction are membrane microdomains[J].J Cell Sci,2001,113(Pt10):1771-81.
[5]彭镜,尹飞.血脑屏障连接复合体与脑损伤[J].国外医学.神经病学分册,2005,32(1):19-22.
[6]Stamatovic SM,Shakui P,Keep RF,et al.Monocyte chemoattractant protein-1regulation of blood-brain barrier permeability[J].J Cereb Blood Flow Metab,2005,25(5):593-606.
[7]彭镜,尹飞,甘娜.内毒素脂多糖对体外血脑屏障模型通透性的影响及其机制研究[J].中华医学杂志,2006,86(27):1924-6.
[8]彭镜,尹飞,李玉飞.川芎嗪对内毒素脂多糖诱导的体外血脑屏障模型通透性增高的保护作用及其机制[J].解剖学杂志,2007,30(5):594-6.
[9]Chavez-Bueno S,McCracken GH.Bacterial meningitis in children[J].Pediatr Clin North Am,2005,52(3):795-810.
[10]Elbashir SM,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J].Nature.2001,411(6836):494-8.
[11]程光,张翔,鲍炜,等.RNA干扰基因敲除MAGE-1在恶性胶质瘤U-87细胞中的初步研究[J].医学研究生学报,2006,19(4):292-7.
[12]杨翔云,张勇,赖小刚,等.人CLC-2基因小分子干扰RNA真核表达载体的构建和鉴定[J].医学研究生学报,2006,19(4):487-91.
[13]Tuschl T.Expanding small RNA interference[J].Nat Biotechnol,2002,20(5):446-8.
[14]Sin JI,Kim JJ,Zhang D,et al.Modulation of cellular responses by plasmid CD40L:CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4~+ T cell-mediated protective immunity against herpes simplex virus type 2 in vivo[J].Hum Gene Ther,2001,12(9):1091-102.
[15]褚晓源,王杰军,陈龙邦,等.小鼠肠癌RNA转染mML-12修饰的树突状细胞诱发特异性细胞毒性T淋巴细胞的研究[J].医学研究生学报,2007,20(1):15-19.
[1]Wegiel J,Imaki H,Wang KC,et al.Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPswtg mice[J].Brain Res,2004,1022(1-2):19-29.
[2]Malm TM,Koistinaho M,P(a|¨)repalo M,et al.Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice[J].Neurobiol Dis,2005,18(1):134-42.
[3]Kim SU,de Vellis J.Microglia in health and disease[J].J Neurosci Res,2005,81(3):302-13.
[4]Saito T,Iwata N,Tsubuki S,et al.Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation[J].Nat Med,2005,11(4):434-9.
[5]Simard AR,Soulet D,Gowing G,et al.Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease[J].Neuron,2006,49(4):489-502.
[6]Cardona AE,Huang D,sasse ME,et al.Isolation of murine microglial cells for RNA analysis or flow cytometry[J].Nat Protoc,2006,1(4):1947-51.
[7]Giuhan D,Baker TJ.Characterization of ameboid microglia isolated from developing mammalian brain[J].J Neurosci,1986,6(8):2163-78.
[8]Giulian D,Li J,Barrel S,et al.Cell surface morphology identifies microglia 88 a distinct class of mononuclear phagocyte[J].J Neurosci,1995,15(11):7712-26.
[9]雷万龙,袁群芳,张怀波,等.啮缺血性半影区胶质细胞和神经元重组的形态学观察[J].中山医科大学学报,2002,23:29-32.
[10]Zhang ZG,Chopp M,Powers C.Temporal profile of microglial response following transient(2h) middle cerebral artery occlusion[J].Brain Res,1997,744:189-98.
[11]Ward SA,Ransom PA,Booth PL,et al.Characterization of ramified microglia in tissue culture 1 pinecytosis and motility[J].J Neurosci Res,1991,29(8):13-28.
[12]Vila M,Jackson Lewis V,Guegan C,et al.The role of glial cells in Parkinson's disease [J].Curr Opin Neurol,2001,14(4):483-9.
[13]Kerschensteiner M,Stadelmann C,Dechant G,et al.Neurotrophic cross-talk between the nervous and immune systems;implications for neurological diseases[J].Ann Neurol,2003,53(3):292-304.
[14]Blasi E,Barluzzi R,Bocchini V,et al.Immortalization of murine microglial cells by a v-mf/v-myc carrying retrovirus[J].J Neuroimmunol,1990,27:229-37.
[1]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34:491-500.
[2]LiuB,Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention[J].J Pharmacol Exp Ther,2003,304:1-7.
[3]Pocock JM,Liddle AC.Microglial signalling cascades in neurodegenerative disease [J].ProgBrainRes,2001,132:555-65.
[4]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke[J].Ernst Schering Res Found Workshop,2002,105:32.
[5]Hanisch UK.Microglia as a source and target of cytokines[J].Glia,2002,40:140-55.
[6]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects[J].Microsc Res Tech,2001,54:47-58.
[7]Seabrook TJ,Jiang L,Maier M.et al.Minocycline affects microglia activation,p deposition,and behavior in APP-mice[J].Glia,2006,53:776-82.
[8]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid B fibril formation and human microglial activation[J].Glia,2006,53:233-40.
[9]Xia MQ,Qin SX,Wu LJ.et al.Immunohistochemical study of the 5-chemokine receptors CCR3 and CCR5 and their figands in normal and Alzheimefs disease brains[J].Am J Pathol,1998,153:31-7.
[10]Xia MQ,Bacskai BJ,Knowles RB,et al.Expression of the chemokine receptor CXCR3on neurons and the elevated expression of its ligand IL-10 in reactive astrocytes:fnvitro ERK112activation and role inAlzheimer's disease[J].J Neuroimmunol,2000,108:227-35.
[11]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell iniury via a nitric oxide mechanism[J].J Immunol,1992,149:2736-41.
[12]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease[J].Biochim Biophys Acta,1997,1362:77-86.
[13]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor B is toxic to embryonic mesencephalic dopamine neurons[J].Exp Neurol,2001,169:219-30.
[14]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration[J].Ann NY AcADSd,2002,962:318-31.
[15]Frautschy SA,Cole GM,Baird A.Phagocytosis and deposition of vascular 5-amyloid in rat brains injected with Alzheimer β amyloid[J].Am J Pathol,1992,140:1389-99.
[16]Weldon DT,Rogers SD,Ghilardi JR,et al.Fibrillar B-amyloid induces microglial phagocytosis,expression of inducible nitric oxide synthase and loss of a select population of neurons in the rat CNS in vivo[J].J Neurosci,1998,18:2161-73.
[17]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid p protein deposition[J].ActaNeuropathol(Bed),1997,94:316-22.
[18]Meda L,Cassatella MA,Szendrei GI,et al.Activation of mi croglial cells by B-amyloid protein and interferon-γ[J].Nature,1995,374:647-50.
[19]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial:identification of a proteinase inhibitor that increase microglial cell number[J].Mol Brain Res,1998,56:99-107.
[20]Lazar G.The reticuloendothelial-blocking effect of rare earth metals in rats.[J].J Reticuloendothel Soc,1973,13(3):231-7.
[21]Husztik E,Lazar G,Parducz.Electron microscopic study of Kupffer phagocytosis blockade induced by gadolinium chloride[J].Br J Exp pathol,1980,61(6):624-30.
[22]Roland CR,Mangino MJ,Flye MW.Lanthanide blockade of antigen-presenting cells suppresses lymphocyte proliferation by inducing nitric oxide synthesis[J].J Surg Res,1993,54(5):401-10.
[23]Mizgerd JP,Molina RM,Stearns RC,et al.Gadolinium induces macrophage apoptosis[J].J Leukoc Biol,1996,59(2):89-95.
[24]Laskin D L,Gardner C R,Price V F,et al.Modulation of macrophage function ingablogates the acute hepatotoxicity of acetaminophen[J].Hepatology,1995,21(4):1045-50.
[25]Roland C R,Naziruddin B,Mohanakumar T,et al.Gadolinium chloride inhibits Kupffer cell nitric oxide synthase(iNOS) induction[J].J Leukoc Biol,1996,60(4):487-92.
[26]Knecht K T,Adachi Y,Bradford B U,et al.Free radical adducts in the bile of rats treated chronically with intragastric alcohol:inhibition by destruction of Kupffer cells[J].Mol Pharmacol,1995,47(5):1028-34.
[27]Rai R M,Zhang J X,Clemens M G,et al.Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro-and anti-inflammatory cytokines[J].Shock,1996,6(4):243-7.
[28]Vollmar B,Ruttinger D,Wanner G A,et al.Modulation of kupffer cell activity by gadolinium chloride in endotoxemic rats[J].Shock,1996,6(6):434-41.
[1]Stoll G,J ander S.The role of microglia and macropha ges in the pathophysiology of the CNS[J].ProgNeurobiol,1999,58(3):233-47.
[2]Pyeongiae L,Jongseok L,Sunshin K,et al.NO as an autocrine mediator in the apoptosis of activated microglialcells:correlation between activation and apoptosis of microglial cells[J].Brain Research,2001,892(2):380-5.
[3]Ferrari D.Chiozzi P,Falzoni S,et al.ATP-mediated cytotoxicity in microglial cells [J].Neuropharmacology,1997,36(9):1295-301.
[4]Xiao BG,Bai XF,Zhang GX,et al.Transforming growth factor-betal induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J].Neurosci Lett,1997,226(2):71-4.
[5]Ogata T,Schubert P.Programmed cell death in rat microglia is controlled by extracellular adenosine[J].NeuroseiLett,1996,218(2):91-4.
[6]Kingharn P J,Pocock JM.Microglial apoptosis induced by chromogranin A is mediated by mitochondrial depolarisation and the permeability transition but not by cytochrome c release.[J].J Neuro Chem,2000,74(4):1452-62.
[7]Jung DY,Lee H,Jung BY,et al.TLR4,but not TLR2,signals autoregulatory apoptosis of cultured microglia:a critical role of IFN-beta as a decision maker[J].J Immunol,2005,174(10):6467-76.
[8]Hu S,Sheng WS,Lokensgard JR,et al.Morphine induces apoptosis of human microglia and neurons.[J].Neuroscience Letters,2002,42(6):829-36.
[1]Jin Y,Fan Y,Yah EZ,et al.MAP kinase superfamily in amyloid β-protain fragment 25-35 induced inflammation and apoptosis in rat hippocampus in vivo Chin[J].J Pharmacol Toxicol,2005,19(3):161-8.
[2]Sundaratajan S,Gambea,Victor NA.et al.Peroxisome proliferator activated receptorgamma ligands reduce inflammation and infarction size in transient focal ischemia [J].Neuroscience,2005,130:685-696.
[3]Widmann C,Gibson S,Jarpe MB,et al.Mitogen-activated protein kinase:conservation of a three-kinase module from yeast to human[J].Physiol Rev,1999,79(1):143-180.
[4]Jeohn GH,Cooper CJ,Wilson B,et al.p38 MAP kinase is involved in Lipopoly-saccharide -induced dopaminergie neuronal cell death in rat meseneephalic neuron-glia cultures [J].Ann NY Acad Sci,2002,962:332-46.
[5]Bhat NR,Zhang P,Lee JC,et al.Extracellular signal-regulated-kinase and p38subgroups of mitogen-activated protein kinases regulateinducible nitric oxide synthase and tumor necrosis factor gene expressionin endotoxin-stimulated primary glial cultures[J].J Neurosci,1998,18:1633-41.
[6]Tikka T,Fiebich BI,Goldsteins G,et al.Minocycline,a tetracycline derivative,is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia [J].J Neurosci,2001,21:2580-8.
[7]Sundararajan S,Gamboa JL,Victor NA,et al.Peroxisome proliferator activated receptor gamma ligands reduce inflammation and infarction size in transient focal ischemia [J].Neuroscience,2005,130:685-96.
[8]Swatton JE,SellersLA,FaunRL,et al.Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain[J].Eur J Neurosci,2004.19(10): 2711-9.
[9]Sun A,Liu M,Nguyen XV,et al.P38 MAP kinase is activated at early stages in Alzheimer's disease brain[J].Exp Neural,2003,183(2):394-405.
[10]Otth C,Mendeza-Naranjo A,Mujica L,et al.Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease[J].Neuro report,2003,14(18):2403-9.
[11]Schechter R,Beju D,Miller KE.The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse[J].Biochem Biophys Res Commun,2005,34(4):979-86.
[12]Foey AD,Parry SL,Williams LM,et al.Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha:role of the p38 and p42/44 mitogen-activated protein kinases[J].J Immunol,1998,160(2):920-8.
[13]Swantek JL,Cobb MH,Geppert TD.Jun N-terminal kinase/stress-activated protein kinase(JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha(TNF-alpha) translation:glucocorticoids inhibit TNF-alpha translation by blocking JNK/ SAPK[J].Mol Cell Biol,1997,17(11):6274-82.
[14]Jians Y,Liu AN,Huang QB,et al.p38 MAPK signal is necessary for TNF-α gene expression in RAW cells[J].Acta Biochim Biophys Sin,1999,31(1):9-15.
[15]Minogue AM,Schmid AW,Fogarty MP,et al.Activation of the c-Jun N-terminal kinase signaling cascade mediates the efect of amyloid-beta on long term potentiation and cell death in hippocampus:a role for interleukin-1beta[J].Bid Chem,2003,278(30):27971-80.
[16]Shoji M,wakami N,Takeuchi S,et al.JNK activation is associate with intracellular beta-amyloid accumulation[J].Brain Res Mol Brain Res,2000,85:221-33.
[17]Savage MJ,Un YG,Cialela JR,et al.Activation of c-Jun Nterminal kinase and p38 in an Klzheimerg disease model is associated with amyloid deposition[J].Neurosci,2002,22:3376-85.
[18]Abramo C,Massone S,Zingg JM,et al.Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death[J].Biochem,2005,391:693-8.
[19]Jiang Y,Liu AN,Zhang L,et al.Activation of p38 mitogen-activated protein kinasein duced by lipopolysaccharide and its the in TNF-α geneex pression[J].J Med Coll PL A,1999,14(2):138-43.
[20]Zhao M,Liu YW,Liu AH,et al.Signal transduction in TNF-α inducted c-jun geneex pression[J].Acta Biochim Biophys Sin,2000,32(3):59-65.
[21]Guan Z,Baier LD,Morrison AR.p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1beta[J].J Biol Chem,1997,272(12):8083-9.
[22]Takahashi.S,Kapas.I,Fang J,et al.Somnogenic relationships between tumor necrosis factor and interleukin 1[J].Am J Physiol,1999,276:1132-40.
[23]Seon H.Kim,Carolyn J,Smith,et al.Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1β production[J].Neurobiology of Aging,2004,25:431-9.
[1]Mark PM.NF-κB in the survival and plasticity of neurons[J].Neurochemical Res,2005,30(6/7):883-93.
[2]陈彬,罗勇.血管内皮细胞中核因子-κB对靶基因的转录调节[J].国外医学脑血管疾病分册,2004,12(12):936-9.
[3]颜因,罗勇.脑缺血炎症反应与星形胶质细胞的关系[J].中国康复理论与实践,2006,12(10):867-70.
[4]何兰英,罗勇.脑缺血再灌注后神经元中核因子-κB对靶基因的转录调节[J].神经疾病与精神卫生,2007,7(1):45-48.
[5]Karin M.How NF-kappaB is activated:the role of the IkappaB kinase(IKK) complex [J].Oncogene,1999,18(49):6867-74.
[6]Kaltschmidt B,Uherek M,Volk B,et al.Transcription factor NF-κB is activated in primary neurons by amyloid β peptides and in neurons surrounding early plaques from patients with Alzheimer disease[J].Proc Natl Acad Sci USA,1997,94:2642-7.
[7]Barger SW,Mattson MP.Tumor necrosis factor α and β protect neurons against amyloid β-peptide toxicity:evidence for involvement of κB-binding factor and attenuation of peroxide and Ca~(2+) accumulation[J].Proc Natl Acad Sci USA,1995,92:9328-32.
[8]Akama KT,Albanese C,Pestell RG,et al.Amyloidβpeptide stimulates nitricoxide production in astrocytes through an NF-κB-dependent mechanism[J].Proc Natl Acad Sci USA,1998,95:5795-800.
[9]Lee HJ,Kim SH,Kim KW,et al.Antiapoptotic role of NF-κB in the auto-oxidized dopamine-induced apoptosis of PC12 cells[J].J Neurochem,2001,76:602-9.
[10]Panet H,Barzilai A,Daily D,et al.Activation of nuclear transcription factor kappa B(NF-κB) is essential for dopamine-induced apoptosis in PC12 cells[J].J Neurochem,2001,77:391-8.
[11]Mattson MP,Camandola S.NF-κB in neuronal plasticity and neuro degenerative disorders[J].J Clin Invest,2001,107:247-54.
[1]林明群,张宗梁.巨噬细胞免疫调节信号-PKA与PKC对MAPK信号通路的调节[J].生物化学和生物物理学报,1999,31(6):701-6.
[2]Shames B D,Selzman C H,Pulido E J,et al.LPS-Induced NF-kappaB activation and TNF alpha release in human monocytes are protein tyrosine kinase dependent and proten kinase C independent[J].J Surg Res,1999,83(1):69-74.
[3]White J E,Lin H Y,Davis F B,et al.Differential induction of tumor necrosis factor alpha and manganese superoxide dismutase by endotoxin in human monocytes:role of protein tyrosine kinase,mitogen-activated protein kinase,and nuclear factor kappaB[J].J Cell Physiol,2000,182(3):381-9.
[4]Giles E H,Fiona J L,Hilmar B,et al.Naclear calcium signaling controls CREB-mediated gene expression triggered by synaptic actitity[J].Nature Neuroscience,2001,4(3):261-7.
[5]Elliott AC.Recent developments in non-excitable cell calcium entry[J].Cell Calcium,2001,30(2):73-93.
[6]金胜威,张力,叶笃筠等.脂氧素对脂多糖诱导的巨噬细胞游离钙浓度变化及活性氧的影响[J].中国病理生理杂志,2005,21(8):1651.
[7]肖殿模,吕文戈,王小鲁等.内毒素对细胞钙摄取及胞浆游离钙浓度的影响[J].中国危重病急救医学,1992,4(2):71-3.
[8]Kawahara M,Kuroda Y.Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein:channel formation and disruption of calcium homeostasis[J].Brain Res Bull,2000,53(4):389-97.
[9]Suh YH.An etiological role of amyloidogenic carboxy-terminat fragments of the beta-amyloid precursor protein in Alzheimer's disease [J].J Neurochem,1997,68;1781-91.
[10]Ca C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chroinc application of beta-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203:61-65.
[11]Guo Q,Robinson N,Mattson M.Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant prusenilin-1 by activation of NF-kappa B and stabilization of calcium homeostasis [J].J Biol Chem,1998,273:12341-51.
[12]Whitson JS,Appel SH.Neurotoxicity of amyloid-beta protein in vitro is not alerted by calcium channel blockade [J].Neurobiol Aging,1995,16:5-10.
[1]Small GW,Rabins PV,Barry PP,et al.Diagnosis and treatment of Alzheimer disease and related disorders.Consensus statement of the American Association for Geriatric Psychiatry,the Alzheimer's Association,and the American Geriatrics Society[J].JAMA,1997,278(16):1363-71.
[2]Baskin DS,Browning JL,Pirozzolo FJ,et al.Brain choline acetyl transferase and mental function in Alzheimer's disease[J].Arch Neual,1999,56(9):1121-3.
[3]Olson RE,Copeland RA.Progress towards testing the amyloid hypothesis:inhibitors of APP processing[J].Curr Opin Drug Discov Devel,2001,4(4):390-401.
[4]Mcquade R,Young A H.Future therapeutic targets in mood disorders:the glucocorticoid receptor[J].Br J Psychiatry,2000,177(2):390-5.
[5]Markesbery WR.The role of oxidative stress in Alzheimer's disease[J].Arch Neurol,1999,56(12):1449-52.
[6]李权益,高薮幔.分子医学-艾滋病、癌症、老年痴呆症[M].台湾:合记图书出版社,1977,135-80.
[7]Weller RO,Massey A,Kuo YM,et al.Cerebral amyloid angiopathy:accumulation of a beta in interstitial fluid drainage pathways in Alzheimer's disease[J].Ann N Y AcADSci,2000,903:117.
[8]田金洲,时晶,程龙,等.阿尔茨海默病患者脑淀粉样血管病变[J].中华老年医学杂志,2003,22(11):708-10.
[9]Cacabelos R.The application of functional genomics to Alzheimer's disease[J].Pharmcaogenomics,2003,4(5):597-621.
[10]Hardy J,Dennis J.The amyloid hypothesis of Alzheimer's disease:progress and problems on the roADto therapeutics[J].Science,2002,297(5508):353-6.
[11]YamagataK,UrakamcK,IredaK,et al.High expression of apolipo proteinE mRNA in the brains with sporadic Alzheimer's disease[J].Dement Geriatr CognDisord,2001,12(2):57-62.
[12]Raygani AV,Zahrai M,Raygani AV,et al.Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran,Iran[J].Neurosci Lett,2005,375(1):1-6.
[13]TrommerBL,Shah C,Yun SH,et al.ApoE isoform-specific effects on LTP:block adeby oligomeric amyloid-betal-42[J].NeurobiolDis,2005,18(1):75-82.
[14]Trittmatter WJ.Apolipoprotein E and Alzheimer's disease:signal transduction mechanisms[J].Biochem SocSymp,2001,(67):101-9.
[15]Ezquerra M,Carnero C,Blesa R,et al.Anovel presenilinl mutation(Leu166Arg)associated withearly onset alzheimer disease[J].J Arch Neurol,2000,57(4):485-8.
[16]Queralt R,Ezquerra M,Castell vi M,et al.Detection of the presenilin 1 genemutation (ML39T) in early onset familial Alzheimer disease in Spain [J].Neurosci Lett,2001,299(3):239-41.
[17]JoannaL,JankowskyJL,FadaleDJ,et al.Mutant presenilins specifically elevate the levels of the 42residue beta-amyloid peptidein vivo:evidence for augmentation of a42-specific gamma secretase [J].Hum Mol Genet,2004,13(2):159-70.
[18]Alvarez V,Alvarez R,Lahoz CH,et al.Association between an alpha(2) macroglobulin DNApolymorphismandlate-onset alzheimer's disease [J].Biochem Biophys ResCommun,1999,264(1):48-50.
[19]KosterMN,DermautB,CrutsM,et al.The alpha2-macroglobulingenein AD:apopulation-based study and meta-analysis [J].Neurology,2000,55(5):678-84.
[20]ZappisM,CittadellaR,Mannal,et al.Genetic association of alpha2-macroglobul in polymorphisms with ADin southern Italy [J].Neurology,2002,59(5):756-8.
[21]WangJZ,Grundke-IqbalK.Glycosylation of microtubule-associated protein tau:an abnormal posttranslational modification in Alzheimer's disease [J].Nat Med,1996,2(8):871-5.
[22]Mayeux R,Lee JH,Romas SN,et al.Chromosome-12 mapping of late-onsef alzheimer disease among Caribbean Hispanics [J].Am J Hum Genet,2002,70(1):237-43.
[23]HerzJ.LRP:Abright beaconat the blood-brain barrier [J].JClinInvest,2003,112(10):1483-5.
[24]Hyoung Lee,Gemma C,Mark S,et al.Challenging the amyloid cascade hypo-thesissenile plaques and amyloid-P asprotective adaptations to Alzheimer disease [J].AnnNYAcadSci,2004,1019:1-4.
[25]Glenner GG,Wong CW.Alzheimer's disease:initial report of the purification and characterization of an ovelcerebro vascular amyloid protein [J].Biochem Biophys Res Commun,1984,120(3):885-90.
[26]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis [J].Science,1992,256(5054):184-5.
[27]Kang J,Lemaire H G,Unterbeck A,et al.The precursor of Alzheimer's disease amyloid A4 protein resembles a cellsurface receptor [J].Nature,1987,325(6106):733-6.
[28]Buxbaum JD,Liu KN,Luo Y,et al.Evidence that tumor necrosis factor a converting enzyme is involved in regulated a-secretase cleavage of the Alzheimer amyloid protein precursor [J].J Biol Chem,1998,273(43):27765-7.
[29]Vassar R,Bennett BD,Babu-Khan S,et al.β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE [J].Science,1999,286(5440):735-41.
[30]Farzan M,Schnitzler CE,VasilievaN,et al.BACE2,aβ-secretase homolog,cleaves at the β site and within the amyloid-p region of the amyloid-P precursor protein [J].Proc Natl AcADSci USA,2000,97(17):9712-7.
[31]Borchelt D R,ThinakaranG,Eckman CB,et al.Familial Alzheimer's disease-linked presenilin1variantselevate Aβ-42/1-40 ratio in vitro and in vivo [J].Neuron,1996,17(5):1005-13.
[32]Herreman A,Serneels L,Annaert W,et al.Total inactivation of g-secretase activity in presenilin-deficientembryonicstem cells [J].Nat Cell Biol,2000,2(7):461-2.
[33]Eckman CB,Mehta ND,Crook R,et al.A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of Aβ 42(43) [J].Hum Mol Genet,1997,6(12):2087-9.
[34]Suzuki N,Cheung TT,Cai XD,et al.An increased percentage of long amyloid b-protein secreted by familial amyloid β protein precursor (β APP717) mutants.Science,1994,264(5163):1336-40.
[35]Kwok JB,Li QX,Hallupp M,et al.Novel Leu723Pro amyloid precursor protein mutation increases amyloid b42(43) peptide levels and induces apoptosis.Ann Neurol,2000,47(2):249-53.
[36]Cai XD,Golde TE,Younkin S G.Release of excess amyloid b protein from a mutant amyloid b protein precursor [J].Science,1993,259(5094):514-16.
[37]Haass C,Hung AY,Selkoe DJ,et al.Mutations associated with alocus for familial Alzheimer's disease resultin alternative processing of amyloid b-protein precursor [J].J Biol Chem,1994,269(26):17741-8.
[38]Scheuner D,Eckman C,Jensen M,et al.Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease [J].Nat Med,1996,2(8):864-70.
[39]De Strooper B,Saftig P,Craessaerts K,et al.Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].Nature,1998,391(6665):387-90.
[40]Mohajeri MH,Saini KD,Nitsch RM.Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology [J].J Neural Transm,2004,111(3):413-25.
[41]Gillespie SL,Golde TE,Younkin SG Secretory processing of the Alzheimer amyloid b/A4 protein precursor is increased by protein phosphorylation [J].Biochem Biophys Res Commun,1992,187(3):1285-90.
[42]Nitsch RM,Slack BE,Wurtman RJ,et al.Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinicacetyl choline receptors [J].Science,1992,258(5080):304-7.
[43]Villa A,Latasa M J,Pascual A.Nerve growth factor modulates the expression and secretion of β-amyloid precursor protein through different mechanisms in PC 12 cells [J].J Neurochem,2001,77(4):1077-84.
[44]Racchi M,Mazzucchelli M,Porrello E,et al.Acetylcholinesterase inhibitors:novel activities of old molecules [J].Pharmacol Res,2004,50(4):441-51.
[45]Simons M,Keller P,De Strooper B,et al.Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons.Proc Natl AcADSci USA,1998,95(11):6460-4.
[46]Yankner BA,Dawes LR,Fisher S,et al.Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.Science,1989,245(4916):417-20.
[47]Frautschy SA,Baird A,Cole G M.Effects of injected Alzheimer β-amyloid cores in rat brain [J].Proc Natl AcADSci USA,1991,88(19):8362-6.
[48]Pike CJ,Walencewicz AJ,Glabe C G,et al.In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity [J].Brain Res,1991,563(1-2):311-4.
[49]Lesne S,Koh M T,Kotilinek L,et al.A specific amyloid-b protein assembly in the brain impairs memory [J].Nature,2006,440(7082):352-7.
[50]Verdier Y,Zarandi M,Penke B.Amyloid b-peptide interactions with neuronal and glial cell plasma membrane:bindingsites and implications for Alzheimer's disease.J Pept Sci,2004,10(5):229-48.
[51]Kim HS,Lee J H,Lee J P,et al.Amyloid b peptide induces cytochrome C release from isolated mitochondria [J].Neuroreport,2002,13(15):1989-93.
[52]Probst A,Langui D,Ulrich J.Alzheimer's disease:a description of the structural lesions[J].BrainPathol,1991,1(4):229-39.
[53]Meda L,Bernasconi S,Bonaiuto C,et al.β-amyloid (25-35) peptide and IFN-g synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells [J].J Immunol,1996,157(3):1213-8.
[54]Mark R J,Hensley K,Butterfield D A,et al.Amyloid b-peptide impairs ion-motive ATPase activities:evidence for a role in loss of neuronal Ca2+ homeostasis and cell death [J].J Neurosci,1995,15(9):6239-49.
[55]Davidson RM,Shajenko L,Donta TS.Amyloid β-peptide(ApP) potentiates a nimodipine-sensitive L-type barium conductance in NlE-115 neuroblastoma cells [J].Brain Res,1994,643(1-2):324-7.
[56]Mattson MP,Cheng B,Davis D,et al.β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity [J].J Neurosci,1992,12(2):376-89.
[57]Behl C,Davis JB,Lesley R,et al.Hydrogen peroxide mediatesamyloid b protein toxicity [J].Cell,1994,77(6):817-27.
[58]Butterfield DA,Hensley K,Harris M,et al.beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion:implications to Alzheimer's disease [J].Biochem Biophys Res Commun,1994,200(2):710-5.
[59]Cafe C,Torri C,Bertorelli L,et al.Oxidative stress after acute and chronic application of β-amyloid fragment 25-35 in cortical cultures [J].Neurosci Lett,1996,203(1):61-65.
[60]Mattson MP.Pathways towards and away from Alzheimer's disease [J].Nature,2004,430(7000):631-639.
[61]Casley CS,Land JM,Sharpe MA,et al.β-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons [J].Neurobiol Dis,2002,10(3):258-67.
[62]Blass JP.Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? [J].J Neurosci Res,2001,66(5):851-6.
[63]Takashima A,Honda T,Yasutake K,et al.Activation of tau protein kinase I/glycogen synthase kinase-3b by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons [J].Neurosci Res,1998,31(4):317-23.
[64]Gotz J,Chen F,van Dorpe J,et al.Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Ap 42 fibrils [J].Science,2001,293(5534):1491-5.
[65]Ferrari A,Hoerndli F,Baechi T,et al.β-Amyloid induces paired helical filament-like tau filaments in tissue culture [J].J Biol Chem,2003,278(41):40162-8.
[66]Olney J W,Wozniak D F,Farber N B.Excitotoxic neurodegeneration in Alzheimer disease.New hypothesis and new therapeutic strategies [J].Arch Neurol,1997,54(10):1234-40.
[67]Iwata N,Tsubuki S,Takaki Y,et al.Metabolic regulation of brain Ab by neprilysin [J].Science,2001,292(5521):1550-2.
[68]Perez A,Morelli L,Cresto JC,et al.Degradation of soluble amyloid b-peptides 1-40,1-42,and the Dutch variant 1-40 by insulin degrading enzyme from Alzheimer disease and control brains [J].Neurochem Res,2000,25(2):247-55.
[69]Nawrot B.Targeting BACE with small inhibitory nucleic acids-a future for Alzheimer's disease therapy? [J].Acta Biochim Pol,2004,51(2):431-44.
[70]Patey SJ.The role of heparan sulfate in the generation of Aβ [J].Drug News Perspect,2006,19(7):411-6.
[71]Steinhilb ML,Turner R S,Gaut J R.The protease inhibitor,MG132,blocks maturation of the amyloid precursor protein Swedish mutant preventing cleavage by b-secretase [J].J Biol Chem,2001,276(6):4476-84.
[72]Asai M,Hattori C,Iwata N,et al.The novel b-secretase inhibitor KMI-429 reduces amyloid b peptide production in amyloid precursor protein transgenic and wild-type mice [J].J Neurochem,2006,96(2):533-40.
[73]Lefranc-Jullien S,Lisowski V,Hernandez J F,et al.Design and characterization of a new cell-permeant inhibitor of the b-secretase BACE1 [J].Br J Pharmacol,2005,145(2):228-35.
[74]Zhang HY,Tang XC.Neuroprotective effects of huperzine A:new therapeutic targets for neurodegenerative disease [J].Trends Pharmacol Sci,2006,27(12):619-25.
[75]Soto C.Plaque busters:strategies to inhibit amyloid formation in Alzheimer's disease [J].Mol Med Today,1999,5(8):343-50.
[76]Smith JV,Luo Y.Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761 [J].J Alzheimers Dis,2003,5(4):287-300.
[77]Sierpina VS,Wollschlaeger B,Blumenthal M.Ginkgo biloba [J].Am Fam Physician,2003,68(5):923-6.
[78]Wang R,Yan H,Tang X C.Progress in studies of huperzine A,a natural cholinesterase inhibitor from Chinese herbal medicine [J].Acta Pharmacol Sin,2006,27(1):1-26.
[79]Schenk D,Barbour R,Dunn W,et al.Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse [J].Nature,1999,400(6740):173-7.
[80]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo [J].Exp Neurol,2000,163(2):388-91.
[81]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation [J].Neurochem Int,2001,39(526):341-8.
[82]Grammas P,Ovase R.Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain [J].Am J Pathol,2002,160 (5):1583-7.
[83]Hoozemans J,Veerhuis R,Janssen I,et al.The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia:implications for Alzheimer's disease [J].Brain Res,2002,951(2):218-26.
[84]O'Banion MK,Miller JC,Chang JW,et al.Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murineastrocyte cultures [J].J Neuro chem,1996,66(6):2532-40.
[85]Ho L,Pieroni C,Winger D,et al.Regionaldistribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease [J].J Neurosci Res,1999,57(3):295-303.
[86]Xiang Z,Ho L,Yemul S,et al.Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology [J].Gene Expr,2002,10(526):271-8.
[87]Webster SD,Yang AJ,Margol L,et al.Complement component C1q modulates the phagocytosis of A beta by microglia [J].Exp Neurol,2000,161(1):127-38.
[88]Shen Y,Lue L,Yang L,et al.Complement activation by neurofibrillary tangles in Alzheimer's disease[J].Neurosci Lett,2001,305(3):165-8.
[89]Bradt BM,Kolb WP,Cooper NR.Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide[J].J Exp Med,1998,188(3):431-8.
[90]McGeer EG,Yasojima K,Schwab C,et al.The pentraxins possible role in Alzheimer's disease and other innate inflammatory disease[J].Neurobiol Aging,2001,22(6):843-8.
[91]McGeer PL,Walker DG,Pitas RE,et al.Apolipoprotein E4(ApoE4) but not ApoE3 or ApoE2 potentiates beta-amyloid protein activation of complement in vitro[J].Brain Res,1997,749(1):135-8.
[92]KuoH,IngramDK,WalkerLC,et al.Similaritiesin theage-related hippocampalde position of periodicacid schiff-positive granules in the senescence-accelerated mouse P8 and C57BL/6 mousestrains[J].Neuroscience,1996,74:733-40.
[93]魏小龙,张永祥.老年性痴呆动物模型研究进展[J].中国药理学通报,2000,16:372-6.
[94]Hefti F,Dravid A,Hartikka J.Chronic in traventricular injections of NGF elevate hippocampal choline acetyl transfer as eactivity in adult rats with septo hippocam pallesions [J].BrainRes,1984,293:305-11.
[95]Miyarnoto M,Koto J,NarumiS,et al.Lesions of the rat basal fore brain leads to memory impairments in passive and active avoidance tasks[J].Brain Res,1985,328:97-104.
[96]Sofroniew MV,Pearson RCA.Degeneration of cholinergic neurons in the basal nucleus following kainicor N-methyl-D-asparticacid application to the cerebral cortex in the rat[J].BrainRes,1985,339:186-190.
[97]Fisher A,Hanin I.Potential animal models for senile dementia of Alzheimer's type,with emphasison AF64A-induced cholinotoxicity[J].Annu Rev Pharmacol Toxicol,1986,26:161-81.
[98]NabeshimaT.Trial to produce animal model of Alzheimer's disease by continuous infusion of beta-amyloid protein into the ratcerebral ventricle[J].Nihon Shinkei Seishin Yakurigaku Zasshi,1995,15:411-8.
[99]Alvarez XA,Miguel-Hidnlgo JJ,Fernandez-Novoa L,et al.Introhippocampal injections of the beta-amyloid 1-28 fragment induces behavior aldeficits in rats[J].Methods Find Exp Clin Pharmacol,1997,19(7):471-9,
[100]Florence AL,Gauthier A,Ponsar C,et al.An experimental animal model of aluminium overload[J].Neurodegeneration,1994,3:315-23.
[101]罗焕敏,肖飞.D-半乳糖和三氯化铝诱导小鼠产生类阿尔茨海默病变[J].中国药理学与毒理学杂志,2004,18:22-26.
[102]罗焕敏,陈子晟.一种新的老年痴呆动物模型[J].中国老年学杂志,2003,23:179-82.
[103]Eilam D,Szechtman H,Faigon M,et al.Disintergration of the spatical organization of behavior in experiment alautoimmunede mentia [J].Neuroscience,1993,56:83-91.
[104]Moran PM,Higgins LS,Cordell B,et al.Age-related learning deficits in transgenic mice expressing the751-aminoacid isoform of human beta-amyloid precursor protein [J].Pro Natl AcADSci USA,1995,92:5341-5.
[105]Games D,Adams D,Alessandrini R,et al.Alzheimer-type neuro pathology in transgenic mice over expressing V717F B-amyloid precursor protein [J].Nature,1995,373:523-7.
[106]Hsiao K,Chapman P,Nilsen S,et al.Correlative memory deficits,AB elevation and amyloid plaques in transgenicmice [J].Science,1996,274:99-102.
[107]Selkoe DJ.Translating cell biology into therapeutic advances in Alzheimer's disease [J].Nature.1999 Jun 24;399(6738 Suppl):A23-31.
[108]Bullock R.New drugs for Alzheimer's disease and other dementias [J].Br J Psychiatry,2002,180:135-9.
[109]NabeshimaT,Yamada K.Development of anti-dementia drugs for Alzheimer's disease [J].AdvBehavBiol,2002,51:223-8.
[110]Wolson C,Perrault A,Moride Y,et al.Acase-control analysis of nonsteroidal anti-inflammatory drugs and Alzheimer's disease [J].Neuroepidemiology,2002,21:81-86.
[111]Simpkins JW,Green P,Gridley KE,et al.Role of Esteogen replacement therapy in memory enhancement and prevention of neuronal loss associated with Alzheimer's disease [J].Am J Med,1997,103:19-25.
[112]Pratico D,Uryu K,Leight S,et al.Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis [J].J Neurosci,2001,21:4183-7.
[113]Sano M,Ernesto C,Thomas RG,et al.Acontrolled trial of selegiline,a-tocopherol,or both as treatment for Alzheimer's disease [J].NewEngJMed,1997,336:1216-22.
[114]LiYM,XuM,LaiMT,et al.Photo activated β-secretase inhibitors directed to the activesite covalently label presenilinl [J].Nature,2000,405:689-94.
[115]Esler WP,Kimberly WT,Ostaszewski BL,et al.Transition-state analogue inhibitors of γ-secretase binds directly to pressenilin-1 [J].NatCellBiol,2002,2:428-34.
[116]Dovey HF,John V,Andereson JP,et al.Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain [J].JNeurochem,2001,76:173-81.
[117]Morgan D,Diamond DM,Gottschall PE,et al.Aβ peptide vaccination prevent smemory loss in an animal model of Alzheimer's disease [J].Nature,2000,408:982-5.
[118]Birminghan K,Frantz S.Set back to Alzheimer vaccine studies [J].NatMed,2002, 8:199-200.
[119]Atwood CS,Scarpa RC,Huang X,et al.Characterization of copperinter actions with Alzheimer Aβ peptides-Identification of an attomolar affinity copper binding site on Aβ1-42[J].JNeurochem,2000,75:1219-33.
[120]ChernyR A,LeggJT,CLeamCA,et al.Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by bimert aldepletion [J].J BiolChem,1999,274:23223-8.
[121]Cherny RA,Atwood CS,Xilinas M,et al.Treatment with acopper-zinc chelator marked lyandrapidly inhibitsβ-amyloidaccumulationin Alzheimer's disease transgenic mice [J].Neuron,2001,30:665-76.
[122]FassbenderK,Simons M,Bergmann C,et al.Simvastatin strongly reduces levels of Alzheimer's disease amyloid peptides Aβ42 [J].Natl AcadSci,2001,98:5856-61.
[123]MartineA,Alonso M,CastroA,et al.Firstnon-ATP competitive glycogen synthase kinase3β(GSK-3β)inhibitors as potential drugs for the treatment of Alzheimer's disease [J].J Med Chem,2002,45:1292-99.
[124]Cras P.Recent developments in Alzheimer's disease [J].Acta Clin Belg,2001,56(5):269-78.
[125]Glabe C.Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease [J].J Mol Neurosci,2001,17(2):137-45.
[126]Esiri MM.Is an effective immune intervention for Alzheimer's disease in prospect?[J].Trends Pharmacol Sci,2001,22(1):2-3.
[127]Selkoe D J.The origins of Alzheimer disease:a is for amyloid [J].JAMA,2000,283(12):1615-17.
[128]Benl C.Alzheimer's disease and oxidative stress:implications for novel therapeutic approehes[J].Prog Neurobiol,1999,57(3):301-23.
[129]Alvarez XA,Miguel HJ,Femadez NL,et al.Intrahippocampal injections of the beta-amyloid 1-28 fragment induces behavioral deficits in rats [J].Methods Find Exp Clini Pharmacol,1997,19(7):471-9.
[130]Yan SD,Chen X,Fu J,et al.RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease [J].Nature,1996,382(6593):685-91.
[131]Weninger SC,Yankner BA.Inflammation and Alzheimer disease:the good,the bad,and the ugly [J].Nat Med,2001,7(5):527-8.
[132]Blass JP.Immunologic treatment of Alzheimer's disease [J].N Engl J Med.1999,341(22):1694-1705.
[133]Frenkel D,Kariv N,Solomon B.Generation of auto-antibodies towards Alzheimer's disease vaccination [J].Vaccine,2001,19(17-19):2615-19.
[134]Morgan D,Diamond DM,Gottschall PE,et al.A beta peptide vaccination prevents memory loss in an animalmodel of Alzheimer's disease [J].Nature,2000,408(6815):982-5.
[135]Janus C,Pearson J,McLaurin J,et al.A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease [J].Nature,2000,408(6815):979-82.
[136]Lambert MP,Viola KL,Chromy BA,et al.Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies [J].J Neurochemi,2001,79(3):595-605.
[137]DeMattos RB,Bales KR,Cummins DJ,et al.Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease [J].PNAS,2001,98(15):8850-5.
[138]Bard F,Cannon C,Barbour R,et al.Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease [J].Nat Med,2000,6(8):916-9.
[139]Virginia ML.Aβ immunization:moving Aβ peptide from brain to blood [J].PNAS,2001,98(16):8931-2.
[140]Games D,Bard F,Guido T,et al.Prevention and reduction of AD-type pathology in PDAPP mice immunized with A beta 1-42 [J].Ann NY AcADSci,2000,920:274-84.
[141]Alon M,Ruth M,Victor Z,et al.Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice:Implications for the pathogenesis and treatment of Alzheimer's disease [J].PNAS,2001,98(18):10273-8.
[142]Dan F,Odelia K,Beka S,et al.Immunization against Alzheimer's disease β-amyloid plaques via EFRH phage administration [J].PNAS,2000,97(19):11455-9.
[1]Tuppo EE,Arias HR.The role of inflammation in Alzheimet's disease [J].Int J Bioc hem Cell Biol,2005,37(2):289-305.
[2]Gehrmann J.Microglia:a sensor to threats in the nervous system? [J].Res Virol,1996,147(2-3):79-88.
[3]Flugel A,Bradl M,Kreutzberg GW,et al.Transformation of donor-derived bone marrow precursors into host microglia during auto immune CNS inflammation and during the retrograde response to axotomy [J].J Neurosci Res,2001,66(1):74-82.
[4]SimardAR RivestS.Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia [J].FASEB J,2004,18(9):998-1000.
[5]SimardA R,SouletD,Gowing G.et al.Bonemarrow.de.rived microglia play a critical role in restricting senile plaqueformation in Alzheimer's disease [J].Neuron,2006,49(41):489-502.
[6]Vilhardt F.Microglia:phagocyte and glia cell [J].Int J Biochem CeU Biol,2005,37(1):17-21.
[7]Matin-Tleva JL,Dusart I,Colin C,et al.Microglia promote the death of developing Purkinjecells[J].Neuron,2004,41(4):535-47.
[8]Polazzi E,Contestable A.Reciprocal interactions between microgfiaandneurons:from survival to neuropathology [J].Rev Neurosci,2002,13(3):221-42.
[9]Kreutzberg GW.Microglia:a sensor for pathological events in the CNS [J].Trends Neurosci,1996,19(8):312-8.
[10]Raivich G.Banati R.Brain microglia and blood-derived macrophages:molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease [J].Brain Res Brain Res Rev,2004,46(3):261-81.
[11]Haughey NJ,Nath A,Chan SL,et al.Disruption of neurogenesis by amyloid peptide,and perturbed neural progenitor cell homeostasis,in models of Alzheimer's disease [J].J Neurochem,2002,83(6):1509-24.
[12]Jacobs BL.Adult brain neurogenesis and depression [J].Brain Behav Inunun,2002,16(5):602-9.
[13]Nelson PT,Soma LA,Lavi E.Microglia in diseases of the central nervous system [J].Ann Med,2002,34(7-8):491-500.
[14]LiuB.Hong JS.Role of microglia in inflammation mediated neurodegenerative diseases mechanisms and strategies for therapeutic intervention [J].J Pharmacol Exp Ther,2003,304(1):1-7.
[15]Pocock JM.Liddle AC.Microglial signalling cascades in neurodegenerative disease[J].Prog Brain Res,2001,132:555-65.
[16]Pocock JM,Liddle AC,Hooper C,et al.Activated microglia in Alzheimer's disease and stroke [J].Ernst Schering Res Found Workshop,2002(39):105:32.
[17]Hanisch UK.Microglia as a source and target of cytokines [J].Glia,2002,40(2):140-55
[18]Gebicke-Haerter PJ.Microglia in neurodegeneration:molecular aspects [J].Microsc Res Tech,2001,54(1):47-58.
[19]Seabrook TJ,Jiang L,Maier M,et al.Minocycline affects microglia activation,Abeta deposition,and behavior in APP-tg mice [J].Glia,2006,53(7):776-82.
[20]Familian A,Boshuizen RS,Eikelenboom P,et al.Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation [J].Glia,2006,53(3):233-40.
[21]Xia MQ,Qin SX,Wu LJ,et al.Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains [J].Am J Pathol,1998,153(1):31-7.
[22]Xia MQ,Bacskai BJ,Knowles RB,et al.Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes:in vitro ERK1/2 activation and role in Alzheimer's disease [J].J Neuroimmunol,2000,108(1-2):227-35.
[23]Chao CC,Hu S,Molitor TW,et al.Activated microglia mediate neuronal cell injury via a nitric oxide mechanism [J].J Immunol,1992,149(8):2736-41.
[24]Cassarino DS,Fall CP,Swerdlow RH,et al.Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease [J].Biochim Biophys Acta,1997,1362(1):77-86.
[25]McGuire SO,Ling ZD,Lipton JW,et al.Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons [J].Exp Neurol,2001,169(2):219-30.
[26]Liu B,Gao HM,Wang JY,et al.Role of nitric oxide in inflammation-mediated neurodegeneration [J].Ann NY AcADSd,2002,962:318-31.
[27]Frautschy SA,Cole GM,Baird A.Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid [J].Am J Pathol,1992,140(6):1389-99.
[28]Weldon DT,Rogers SD,Ghilardi JR,et al.Fibrillar beta-amyloid induces microglial phagocytosis,expression of inducible nitric oxide synthase,and loss of a select population of neurons in the rat CNS in vivo [J].J Neurosci,1998,18(6):2161-73.
[29]Sasaki A,Yamaguchi H,Ogawa A,et al.Microglial activation in early stages of amyloid beta protein deposition [J].ActaNeuropathol(Bed),1997,94(4):316-22.
[30]Meda L,Cassatella MA,Szendrei G I,et al.Activation of microglial cells by β-amyloid protein and interferon-γ[J].Nature,1995,374(6523):647-50.
[31]Vincent VA,Tilders FJ,Van Dam AM.Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells:a role for transforming growth factor beta [J].Glia,1997,19(3):190-8.
[32]Aloisi F.Immune function of microglia [J].Gila,2001,36(2):165-79.
[33]Weisman D,Hakimian E,Ho GJ.Intefleukins,inflammation,and mechanisms of Alzheimer's disease [J].Vitam Horm.2006,74:505-30.
[34]Tsirka SE.Clinical implications of the involvement of tPA inneuronal cell death [J].J Mol Med,1997,75(7):341-7.
[35]Tan J,TownT,Paris D,et al.Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation [J].Science,1999,286(5448):2352-5.
[36]Aloisi F,Penna G,Polazzi E,et al.CD40-CD154 interaction and IFN-gamma are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells[J].J Immunol.1999.162(3):1384-91.
[37]Lee da Y,Park KW,Jin BK.Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro:proteolytic and non-proteolytic actions [J].Biochem Biophys Res Commun,2006,346(3):727-38.
[38]Choi SH,Lee DY,Kim SU,et al.Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo:role of microglial NADPH oxidase [J].J Neurosci,2005,25(16):4082-90.
[39]Kim YS,Kim SS,Cho JJ,et al.Matrix metalloproteinase-3:a novel signaling proteinase from apoptotic neuronal cells that activates microglia [J].J Neurosci.2005,25(14):3701-11.
[40]Eder C.Ion channels in mi croglia(brain rnacrophages) [J].Am J Physiol,1998,275(2n pt 1):327-42.
[41]Suzumura A,Sawada M,Takayanagi T.Production of intedeukin-12 and expression of its receptors by murine microglia [J].Brain Res,1998,787(1):139-42.
[42]Koo EH,Park L,Selkoe DJ.Amyloid β-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth [J].Proc Natl AcADSci USA,1993,90(10):4748-52.
[43]Behl C.Amyloid β-protein toxicity and oxidative stress in Alzheimer's disease [J].Cell Tissue Res,1997,290(3):471-80.
[44]Cotter RL,Burke WJ,Thomas VS,et al.Insights into the neurodegenerative process of Alzheimer's disease:a role for mononuclear phagocyte-associated inflammation and neurotoxicity [J].J Leukoc Biol,1999,65(4):416-27.
[45]Casal C,Serratosa J,Tusell JM.Effects of beta-AP peptides on activation of the transcription factor NF-kappaB and in cell proliferation in glial cell cultures [J].Neurosci Res,2004,48(3):315-23.
[46]El Khoury J,Hickman SE,Thomas CA,et al.Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils [J].Nature,1996,382(6593):716-9.
[47]Roy A,Fung YK,Liu X,et al.Upregulacion of micmglial CD11b expression bvnitric Oxide [J].J Biol Chem,2006,281(21):14971-80.
[48]Lorton D.beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium-and G-protein-dependent [J].Mech Ageing Dev,1997,94(1-3):199-211.
[49]Combs CK,Johnson DE,Cannady SB,et al.Identifcation of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of β-amyloid and prion proteins [J].J Neurosci,1999,19(3):928-39.
[50]Streit WJ,Sparks DL.Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits [J].J Mol Med,1997,75(2):130-8.
[51]Bartholdi D,Schwab ME.Expression of proinflammatory cytokine mRNA upon experimental spinal cord injury in mouse:an in situ hybridization study [J].Eur J Neurnsie,1997,9(7):1422-38.
[52]Benveniste EN.Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis.[J].J Mol Med,1997,75(3):165-173.
[53]Casal Ct Serratosa J,Tusell JM.Relationship btm n beta AP peptide aggregation and microlial activation [J].Brain Res,2002,928(1-2):76-84.
[54]Taniwaki Y,KatoM,Araki T,et al.Microglial activation by epileptic activities through the propagation pathway of kainic acidinduced hippocampal seizures in the rat [J].Neurosci Lett,1996,217(1):29-32.
[55]Ferrari D,Chiozzi P,Falzoni S,et al.Purinergic modulation of lL1beta release from microglial cells stimulated with bacterial endotoxin [J].J Exp Med,1997,185(3):579-82.
[56]Kakimura J,Kitamura Y,Takata K,et al.Mioroglial activation and amyloid beta clearance induced by exogenous heat-shock proteins [J].FASEB J,2002,16(6):601-3.
[57]Spleiss O,Appol K,Boddeke HW,et al.Molecular biology of microglia cytokine and chemokine receptors and microbial activation [J].Life Sei,1998,62(17-18):1707-10.
[58]Laurenzl MA,Areuri C,Ressi R,et al.Efects of microenvironment on morphology and function of the microglial cell line BV2 [J].Neurnchem Res,2001,26(11):1209-16.
[59]Kettenmann H,Hoppe D,Gottmann K,et al.Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages [J].J Neurosci Res,1990,26(3):278-87.
[60]Smita TV,Elkalx S,Schiek C,et al.Gene expression in activated brain microglial: identification of a proteinase inhibitor that increase microglial cell number [J].Mol Brain Res,1998,56(1-2):99-107.
[61]Hanasaki K,Yokota Y,Ishizaki J.et al.Resistance to endotoxic shock in phospholipase A2 receptor-defieientmice[J].J Biol Chem,1997,272(52):32792-7.
[62]Paris D,Town T,Mullan M.Novel strategies for opposing murine microbial activation [J].Neurosci Lett,2000,278(1-2):5-8.
[63]Sanz O,Acarin L,Gonzalez B,et al.NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain [J].J Neuroaci Res,2002,67(6):772-80.
[64]Ferrari D,Villalba M,Chiozzi P,et al.Mouse microglial cell express a plasma membrane pore gated by extraeellular ATP [J].J Immunol,1996,156(4):1531-9.
[65]Kaltschmidt C,Lannes-Vieira J,Kreutzberg GW,et al.Transcription factor NF-kappa B is activated in microglia during experimental autoimmune encephalomyelitis.[J].J Neuro Immunol,1994,55(1):99-106.
[66]Fiebich BL,Butcher RD.Protein kinase Cmediated regulation of iNOS expression in cultured microglia [J].J Neuroimmunol,1998,92(1-2):170-8.
[67]Nagai A,Nakagawa E,Hatofi K,et al.Generation and characterization of immortalized human microglial cellines:expression of cytokines and chemokines [J].Neurobiol Dis,2001,8(6):1057-68.
[68]Saha RN,Pahan K.Regulation of inducible nitric oxide synthase gene in glial cells [J].Antioxid Redox Signal,2006,8(5-6):929-47.
[69]Yon Bernhardi R,Eugenin J.Microglial reactivity to β-amyloid is modulated by astrocytes and proinflammatory factors [J].Brain Res,2004,1025(1-2):186-93.
[70]Velez-Pardo C,Ospina GG,Jimenez del Rio M.Abeta[25-35]peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism:involvement of H_2O_2,caspase-3,NF-kappaB,p53 and c-Jun [J].Neurotoxicology,2002,23(3):351-65.
[71]Jang MH,Jung SB,Lee MH,et al.Melatonin attenuates amyloid p25-35-induced apoptosis in mouse microglial BV2 cells [J].Neurosci Lett,2005,380(1-2):26-31.
[72]Nakamura S,Kawamata T,Akiguchi I,et al.Reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry in neocortex and hippocampus in patients with Alzheimer type dementia and aged controls [J].Rinsho Shinkeigaku,1987,27(8):1059-63.
[73]Wilkinson BL,Landreth GE.The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease [J].J Neuro inflammation,2006,3:30.
[74]Adams JD Jr,Klaidman LK,Chang ML,et al.Brain oxidative stress--analytical chemistry and thermodynamics of glutathione and NADPH [J].Curr Top Med Chem,2001, 1(6):473-82.
[75]Qin B,Carrier L,Dubois-Dauphin M,et al.A key role for the microglial NADPH oxidase in APP-dependent killing of neurons [J].Neurobiol Aging,2006,27(11):1577-87
[76]Jekabsone A,Mander PK,Tickler A,et al.Fibrillar beta-amyloid peptide Abeta 1-40 activates microglial proliferation via stimulating TNF-alpha release and H202 derived from NADPH oxidase:a cell culture study [J].J Neuroinflammation,2006,3:24.
[77]Lue LF,Walker DG,Brachova L,et al.Involvement of microgtial receptor for advanced glycation endproducts(RAGE)in Alzheimer's disease:identification of a cellular activation mechanism [J].Exp Neurol,2001,171(1):29-45.
[78]Liu Y,Qin L,Wilson BC,et al.Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons [J].J Pharmacol Exp Ther,2002,302(3):1212-19.
[79]CoraciI S,Husemann J,Berman JW,et al.CD3 6 a class B scavenger receptor,is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils [J].Am J Pathol,2002,160(1):101-12.
[80]Walker DG,Lue LF,Beach TG.Gene expression profiling of amyloid p peptide-stimulated human post-mortem brain microglia [J].Neurobiol Aging,2001,22:957-66
[81]Akiyama H.Abeta,tau and alpha-synuclein and glial cells [J].Nihon Shinkei Seishin Yakurigaku Zasshi,2006,26(1):23-31.
[82]Kitazawa M,Yamasak TR,LaFerla FM.Microglia as a potential bridge between the amyloid β-peptide and tau [J].Ann NY AcADSci,2004,1035:85-103.
[83]Uchihara T,Duyckaerts C,Seilhean D,et al.Exclusive induction of tau2 epitope in microglia/macrophages in inflammatory lesions-tautwopathy distinct from degenerative tauopathies[J].Acta Neuropathol(Bed),2005,109(2):159-64.
[84]Quintanilla RA,Orellana DI,Gonzalez-Billault C,et al.Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway.Exp Cell Res.2004.295(1):245-57.
[85]Li Y,Liu L,Barger SW,et al.Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway.J Neurosci.2003,23(5):1605-11.
[86]Sheng JG,Jones RA,Zhou XQ,et al.Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease:potential significance for tau protein phosphorylation [J].Neurochem Int.2001,39(5-6):341-8.
[87]Kitazawa M,Oddo S,Yam asaki TR,et al.Lipopolysaccha ride-induced inflamm ation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a tran sgenic model of Alzheimer's disease [J].JNeurosci.2005.25(39):8843-53.
[88]Griffin WS,Sheng JG,Roberts GW,et al.Interleukin-1 expression in diferent plaque types in Alzheimer's disease:significance in plaque evolution [J].J Neuropathol Exp Neurol,1995,54(2):276-81.
[89]Apelt J,Schliebs R.β-amyloid-induced glial expression of both pro-and anti inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology [J].Brain Res.2001,894(1):21-30.
[90]Bellucci A,Westwood AJ,Ingram E,et al.Induction of inflammatory mediators and microglial activation in mice transgenic formutant human P301S tau protein [J].AmJPathol,2004,165(5):1643-52.
[91]Holmlund L,Cortes Toro V,Iverfeldt K.Additive effects of amyloid β fragment and interleukin 1β on interleukin 6 secretion in rat primary glial cultures [J].Int J Mol Med,2002,10(3):245-50.
[92]NessaBN,TanakaT,Kamino K,etal.Toll like receptor 3 mediated hyper phosphorylation of tau in human SH-SY5Y neuroblastoma cells [J].Psychiatry Clin Neurosci.2006,60 Suppl 1:S27-33.
[93]Casal C,Serratosa J,Tusell JM.Relationship between beta-AP peptide aggregation and microglial activation [J].Brain Res.2002,928(1-2):76-84.
[94]Takata K,Kitamura Y,Umeki M,et al.Possible involvement of small oligomers of amyloid-beta peptides in 15-deoxy-delta 12,14 prostaglandin J2-sensitive microglial activation [J].J Pharmacol Sci.2003,91(4):330-3.
[95]Hashioka S,MonjiA,Ueda T,et al.Amyloid-beta fibril formation is not necessarily required for microglial activation by the peptides [J].Neurochem Int.2005,47(5):369-76.
[96]Sebastiani G,Morissette C,Lagac(?) C,et al.The cAMP-specific phosphodiesterase 4B mediates Abeta-induced microglial activation [J].Neurobiol Aging.2006,27(5):691-701.
[97]Wilcock DM,Di Carlo G,Henderson D,et al.Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation [J].J Neurosci,2003,23(9):3745-51.
[98]Koenigsknecht J,Landreth G Microglial phagocytosis of fibrillar beta-amyloid through a betal integrin-dependent mechanism [J].J Neurosci.2004,24(44):9838-46.
[99]Von Bernhardi R,Ramirez G,Toro R,et al.Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture [J].Neurobiol Dis.2007,26(1):153-64.
[100]Takata K,Kitamura Y,Yanagisawa D,et al.Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats [J].FEBS Lett.2007,581(3):475-8.