基础医学神经生物学课件神经系统退行性疾病基础

Neurodegenerative Diseases崔德华崔德华（DH Chui,MD,PhD,）博士生导师博士生导师 Neuroscience,Research Institute and Dep.Of Neurobiology Peking University,China Neurodegenerative Diseases崔德华 What Is Neurodegenerative diseases Hereditary and sporadic conditions which are Hereditary and sporadic conditions which are characterized by progressive nervous system characterized by progressive nervous system dysfunction.dysfunction.These disorders are often associated with atrophy These disorders are often associated with atrophy(Apoptosis)of the affected central or peripheral(Apoptosis)of the affected central or peripheral nervous system structures.nervous system structures.崔德崔德华 DH Chui DH ChuiWhat Is Neurodegenerative diseNeurodegenerative DiseasesAlzheimers Disease(AD)APP(chr 21）PS1(chr 14）PS2(chr 1）ApoE(chr 19）Parkinsons Disease(PD)parkin gene alph-synuclein(autosoma)Huntingtons Disease(HD)CAG repead(chr 4）Amyotrophic Lateral Sclerosis,ALS Creutzfeldt-Jakob Disease(CJD)Corticobasal degeneration(CBD)Multi-infarct Dementia(MID)Lewy Body Diseases(LBD)Multiple system atrophy(MSA)Progressive supranuclear palsy(PSP)Picks DiseaseHeredodegenerative Disorders,Paraneoplastic Syndromes,Olivopontocerebellar AtrophiesPostpoliomyelitis Syndrome崔德崔德华 DH Chui DH ChuiNeurodegenerative DiseasesAlzh1.大脑皮层变性大脑皮层变性：包括Alzheimer病、Pick病、CreutzfeldtJakob病(海绵状变性)等。2.锥体外系统变性锥体外系统变性：包括Huntington病、HallervordenSpatz病、Wilson病(肝豆状核变性)、Seitelberger病(神经轴索型营养不良)、进行性肌阵挛型癫痫。病损在中脑与纹状体者有Parkinson(帕金森)病、纹状体黑质变性、进行性核上型麻痹(PSP)等。3.脑干小脑变性脑干小脑变性：包括各种小脑型共济失调、脊髓小脑变性、橄榄桥脑小脑变性(OPCA)、MachadoJoseph病等。4.脊髓变性脊髓变性：包括进行性痉挛性截瘫、进行性后索变性、后侧索联合变性、Friedreich共济失调等。5.运动系统变性运动系统变性：包括各型运动神经元病，如肌萎缩侧索硬化(ALS)、进行性脊髓性肌萎缩(SMA)、进行性球麻痹等。6.自主神经系统变性自主神经系统变性：包括RileyDay症候群(全自主神经功能不全)、ShyDrager症候群等。7.多系统变性多系统变性(MSA)：包括上述1、2、3、6等的混合类型。Neurodegenerative DiseasesClassification 崔德崔德华 DH Chui DH Chui大脑皮层变性：包括Alzheimer病、Pick病、CreuParkinson disease崔德崔德华 DH Chui DH ChuiParkinson disease崔德华 DH Chui崔德崔德华 DH Chui DH Chui崔德华 DH ChuiWhat Is Alzheimer Disease?The Molecular Mechanisms of Alzheimer DiseaseTherapeutic Approach for Alzheimer Disease崔德崔德华 DH Chui DH ChuiWhat Is Alzheimer Disease?TAlzheimer Disease奥古斯特奥古斯特 (51)(51)崔德崔德华 DH Chui DH ChuiAlzheimer Disease奥古斯特(51)崔德华Growth in U.S.Population Aged 65+,75+,and 85+Source:U.S.Census Bureau崔德崔德华 DH Chui DH ChuiGrowth in U.S.Population AgedGenes Associated with Alzheimer Disease崔德崔德华 DH Chui DH ChuiGenes Associated with AlzheimeClassification of Senile DementiaDSM-IV分类1.阿尔茨海默病阿尔茨海默病 (AD)(AD)2.血管性痴呆血管性痴呆 (CVD)(CVD)3.3.脑外伤所致痴呆脑外伤所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆病所致痴呆9.9.物质和躯体病所致痴呆物质和躯体病所致痴呆10.10.其它痴呆其它痴呆(Lewy body dementia)(Lewy body dementia)崔德崔德华 DH Chui DH ChuiClassification of Senile DemenThe AD diagnosisADAD临床床诊断的断的权威威标准主要有准主要有3 3个：个：世界卫生组织的疾病国际分类第10版(international classification of diseases,10th revision,ICD-10)中的标准；美国国立神经、语言疾病和卒中研究所(The National Institute of Neurological and Communicative Disorders,NINCDS)与AD及相关疾病协会(The Alzheimers Disease and Related Disorders Association,ADRDA)制定的标准；美国精神病诊断和统计手册修订第4版(the Diagnostic and Statistical Manual of Mental Disorders,4th edition,Revised,DSM-IV)的标准。#上述3个标准都是当前国际公认的AD诊断标准，临床上可根据需要选择或互相参照使用。其中美国NINCDS-ADRDA制定的标准中，将AD定义为很可能AD(Probable AD)、可能AD(Possible AD)和确定的AD，操作性较好。应用该标准及相关的诊断量表，AD临床诊断的准确率可以提高到90%以上。崔德崔德华 DH Chui DH ChuiThe AD diagnosisAD临床诊断的权威标准主要有ADclinicalsymptomADclinicalsymptom神经症状和体征神经症状和体征认知性症知性症状记忆记忆非非认知性症状知性症状精神和行为症状精神和行为症状失用失用失认失认失语失语执行功能执行功能崔德崔德华 DH Chui DH ChuiAD clinical symptom神经症状和体征认知性症 崔德崔德华 DH Chui DH Chui崔德华 DH ChuiAgentAgentRecognize Recognize sitesiteCompanyCompany samplesample Detect methodDetect methodINNOTEST hTau Aghuman tau,antigen in CSFInnogenetics,Belgium25 L CSFELISA microplate assayINNOTEST PHOSPHO-TAU(181P)tau(181p)Innogenetics,Belgium75 L CSFELISA microplate assayINNOTEST-AMYLOID(1-42)human-amyloid1-42(A1-42)Innogenetics,Belgium25 L CSFELISA microplate assayINNO-LiPA ApoEapolipoprotein E genotypes e2,e3,and e4Innogenetics,Belgiumbloodline probe assayINNO-BIA AlzBio3A1-42,total-tau,P-tau181P Innogenetics,BelgiumUndiluted(75 L)/CSFbead-based multiparameter immunoassayCommercial Biomarker Kits for Diagnosis AD崔德崔德华 DH Chui DH ChuiAgentRecognize siteCompany sam崔德崔德华 DH Chui DH Chui崔德华 DH Chui崔德崔德华 DH Chui DH Chui崔德华 DH ChuiHowDiscrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging崔德崔德华 DH Chui DH ChuiHowDiscrimination Between E 19861986年美国国立精神保健研究所提出年美国国立精神保健研究所提出:AAMIAAMI A Age-ge-A Associated ssociated M Memory emory I Impairmentmpairment 随年龄增加出现非病理性的记忆力下降随年龄增加出现非病理性的记忆力下降 健忘是老年人健忘是老年人脑功能衰弱的表功能衰弱的表现.痴呆痴呆则是病理性的是病理性的脑器器质性智能衰退性智能衰退。崔德崔德华 DH Chui DH Chui 崔德华 DH Chui如何区分老年健忘与早期如何区分老年健忘与早期ADAD健忘是老年人脑功能衰弱的表现，而痴呆则是病理性的脑器质性智能衰退健忘是老年人脑功能衰弱的表现，而痴呆则是病理性的脑器质性智能衰退，遗忘区别遗忘区别 健忘的老年人对做过事情的遗忘总是部分性的；痴呆的遗忘则是完全恶性的，记不起发生过的事情，似乎 此事已完全消失。认知能力认知能力 健忘老人虽然记忆力下降，但对时间、地点、人物关系和周 围环境的认知能力丝毫未减；痴呆老人却丧失了识别周围环境的认知能力，分不清上下午，不知季节变化，不知身在何处，有时甚至找不到回家的路。生活能力生活能力 健忘老人虽会记错日期有时前讲后忘，但他们仍能料理自己 的生活，甚至能照顾家人；痴呆老人随着病情加重，会逐渐丧失生活自理能力。情绪变化情绪变化 健忘老人有七情六欲；痴呆老人的情感世界则变得“与世无争”，麻木不仁。思维变化思维变化 健忘老人对记忆力下降相当苦恼，为了不致误事，常记个备忘录；痴呆老人毫无烦恼，思维越来越迟钝，言语越来越贫乏，缺乏幽 默感，反应迟缓。是否语言丰富，幽默多彩，是区别生理健忘和痴呆的重要标志之一。崔德崔德华 DH Chui DH Chui如何区分老年健忘与早期AD健忘是老年人脑功能衰弱的表现，而痴90y90y崔德崔德华 DH Chui DH Chui90 y崔德华 DH ChuiNo statistically significant differences in the total number of neurons were observed in the non-demented group TheJournalofNeuroscience,July15,1996,16(14):4491?4500崔德崔德华 DH Chui DH ChuiNo statistically significant dProfound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer DiseaseTheJournalofNeuroscience,July15,1996,16(14):4491?4500 The number of neurons in the EC in the AD group(n=10)compared with CDR 5 0 controls(n=10),correlated with the clinical severity of dementia.The difference increased from 32%in the CDR=0.5 subgroup(n=4)to 69%in the CDR=3 subgroup(n=5).崔德崔德华 DH Chui DH Chui Profound Loss of Entorhinal CSchematic representation of regional and laminar NFT formation and neuronal loss in normal aging and ADSCIENCEVOL.278,412-419,1997NFT:densities the yellow flame-shaped structures represent a semiquantitativeEC:entorhinal cortex SP:stratum pyramidale of the CA1 field ITC:inferior temporal cortex SFC:superior frontal cortex崔德崔德华 DH Chui DH ChuiSchematic representation of reWhatisWhatisP PairedairedH HelicalelicalF FilamentsilamentsTauTau？-PHF Tau -崔德崔德华 DH Chui DH ChuiWhat isPaired Helical Filama)The cytoskeleton b)components of the cytoskeleton崔德崔德华 DH Chui DH Chuia)The cytoskeleton b)compoSulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs崔德崔德华 DH Chui DH ChuiSulfo-glycosaminoglycan conten崔德崔德华 DH Chui DH Chui崔德华 DH Chui崔德崔德华 DH Chui DH Chui崔德华 DH ChuiAPP:Amyloid precursor proteinAPP:Amyloid precursor protein崔德崔德华 DH Chui DH ChuiAPP:Amyloid precursor proteiWhat is Presenilin,APP and A?崔德崔德华 DH Chui DH ChuiWhat is Presenilin,APP and Molecular features of presenilin and APP崔德崔德华 DH Chui DH ChuiMolecular features of presenilMolecular features of APP and Abb peptidesAPP:Amyloid precursor protein崔德崔德华 DH Chui DH ChuiMolecular features of APP and presenilin(Psn）A APP secretaseAAAAPresenilin complex崔德崔德华 DH Chui DH Chuipresenilin(Psn）AbAPPsecrAggregation of -amyloid is a multi step process崔德崔德华 DH Chui DH ChuiAggregation of-amyloid is a Courtesy:Prof.C.Glabe,UC Irvine崔德崔德华 DH Chui DH ChuiCourtesy:Prof.C.Glabe,UC IProposed actions of heat shock protein 70 and heat shock protein 40chaperones on amyloid assemblyNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德崔德华 DH Chui DH ChuiProposed actions of heat shockDirect and indirect effects of molecular chaperones on disease protein toxicityNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德崔德华 DH Chui DH ChuiDirect and indirect effects ofProtein misfolding diseases associated with molecular chaperonesNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德崔德华 DH Chui DH ChuiNATURE REVIEWS|NEUROSCIENCE PresenilinA cascades in AD 崔德崔德华 DH Chui DH Chui PresenilinAb cascades in ADTransgenic mice with presenilin 1 mutations hPS1/FVB/N miceMicroinjection method1)FVB/N mice2)2)pAxCAwt-vector3)3)h-PDGF promoter4)4)hPS1-L286V-cDNA5)hPS1-H163R-cDNAChui,DH.etal.NatMed5,560-4.(1999)崔德崔德华 DH Chui DH ChuiTransgenic mice with preseniliDark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid plaque formationChui,DH.etal.NatMed5 5,560-4.(1999)崔德崔德华 DH Chui DH ChuiDark neuron counts are signifiNeurons with intracellular A-positive deposits Chui,D.H.etal.NatMed5,560-4.(1999)崔德崔德华 DH Chui DH ChuiNeurons with intracellular Ab-AnalysisAnalysis of apoptosis by double staining with A of apoptosis by double staining with A42 42 42 42(green)and(green)and TUNEL(red)TUNEL(red)PS1 FADPS1 FAD iAnegative/TUNEL+iApositive/TUNEL+%Mean,SEM*Chuietal,JAlzheimersDis.2001Apr;3(2):231-239 Chui,DH.et al.J of Alzheimer Disease.2001;3:231 崔德崔德华 DH Chui DH ChuiAnalysis of apoptosis by doubl Impairment of LTP in brain of 3 x TG 崔德崔德华 DH Chui DH Chui Impairment of LTP in brain oA A A A Amyloid Amyloid aggregationsaggregationsSenile plaquesPHF-TauPHF-TauNeuronal deathAPPAPPA A A A Alzheimer disease DementiaHypothesis of Amyloid CascadeExtracelluar AbPS-1 mutationPS-1 mutation Pathogenic role of the PS-1 mutation is Up stream of amyloid cascadeEnhanced production of Ab42Intracellular Ab42 Neuronal degenerationAlzheimer disease Dementia崔德崔德华 DH Chui DH ChuiAbAmyloid aggregationsSenile pSummary(1)1.Mutations of presenilin 1(PS-1)enhance the generation of A1A1-42,indicating that PS-1 is involved in amyloidogenesis.2.We firstly found that neurodegeneration was significantly accelerated in older aged mice with mutant PS-1,without amyloid plaque formation.3.There were significantly more neurons containing intracellularly deposited AA in aged mutant transgenic mice.Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade。崔德崔德华 DH Chui DH ChuiSummary(1)Mutations of presenFormation of TAU inclusions in knock-in mice with familial Alzheimers disease(FAD)mutation of presenilin 1(PS1)TanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005崔德崔德华 DH Chui DH ChuiFormation of TAU inclusions inImmunostaining with PS1 and PHF-tauChui et al.J Neurosci Res.1998,1;53(1):99 Chui et al.J Neurosci Res.1998,1;53(1):99 PS1-NAT-8PS1-C AT-8崔德崔德华 DH Chui DH ChuiImmunostaining with PS1 and PHtau(ins.)tau(sol.)PS199PS262PS396PS404PS422AT8Tau-1wPS1mPS1(hetero)mPS1(homo)wPS1mPS1(hetero)mPS1(homo)Western blots of SDS-insoluble and RIPA-soluble materialsTanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005崔德崔德华 DH Chui DH ChuitautauPS199PS262PS396PS404PS42TanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005The formation and accumulation of filamentous tau were Accelerated Accelerated by activating GSk-3by activating GSk-3 n n GSK-3 GSK-3(Ser-9)Western blot of GSK-3 wPS1mPS1(hetero)mPS1(homo)1600014000120001000080006000wildheterohomoRelative activity(cpm/mg protein/min)GSk-3 Activity崔德崔德华 DH Chui DH ChuiTanemura，Chui et al.JBC,2005TSummary(2)PS1 mutations contribute to the onset PS1 mutations contribute to the onset of AD not only by enhancing A1-42 of AD not only by enhancing A1-42 production but by also accelerating production but by also accelerating the formation and accumulation of the formation and accumulation of filamentous tau.filamentous tau.TanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005崔德崔德华 DH Chui DH ChuiSummary(2)PS1 mutations contrPS1 may act as a molecular tether,connecting GSK-3 with important substrates.PS1GSK-3PS1TauTauPS1-cateninPS1 APhosphorylationof tauNFT Cell death Inhibition ofprotein synthesisGSK-3GSK-3GSK-3-cateninA42 productionP53？崔德崔德华 DH Chui DH ChuiPS1 may act as a molecular tetJ.Biol.Chem.,Vol.278,Issue49,48872-48879Domains of p53 that regulate its association with GSK3 崔德崔德华 DH Chui DH ChuiJ.Biol.Chem.,Vol.278,IssuNeuronal Degeneration Activates p53 Promoter？Intracellular A 42崔德崔德华 DH Chui DH ChuiNeuronal Degeneration Activate RT-PCR Analyses of p53 mRNA in APP-Tg(3M,6M and 10M)Oyagi,Asahara,Chui et al.FASEB J.2005Oyagi,Asahara,Chui et al.FASEB J.2005崔德崔德华 DH Chui DH Chui RT-PCR Analyses of p53 mRNA Immunoblotting analysis,immunocytochemical staining and double immunostaining in AD brainOyagi,Asahara,Chui et al.FASEB J.2005Oyagi,Asahara,Chui et al.FASEB J.2005崔德崔德华 DH Chui DH Chui Immunoblotting analysis,imSummary(3)1.Intracellular A 42 directly activated the p53 promoter resulting in p53-dependent apoptosis.2.Remarkably,accumulation of both A 42 and p53 was found in some degenerating-shape neurons in both mice and AD cases.3.Thus,the intracellular A 42/p53 pathway may be directly relevant to neuronal loss in AD.4.4.Intracellular AIntracellular A 42 may cause p53-dependent neuronal 42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter;apoptosis through activation of the p53 promoter;thus demonstrating an alternative pathogenesis in AD.thus demonstrating an alternative pathogenesis in AD.Oyagi,Asahara,Chui et al.FASEB J.2005Oyagi,Asahara,Chui et al.FASEB J.2005崔德崔德华 DH Chui DH ChuiSummary(3)Intracellular A42 Structure of Human GSK3 崔德崔德华 DH Chui DH ChuiStructure of Human GSK3 崔德华 DHGSK-3a a is required for A productionCHO-APP695cellsweretransfectedwithGFPorGSK-3a,andsecretedAb42崔德崔德华 DH Chui DH ChuiGSK-3a is required for Ab prodLithiumblocksALithiumblocksA accumulationinculturedneuronsandinthebrainsofaccumulationinculturedneuronsandinthebrainsofmicemiceoverproducingAoverproducingA peptidespeptidesEmbryonic cortical neurons were infected with SFV containing wild-type APP(APP-WT)or APP-Swedish(KM670/671NL),then treated with LiCl for 24 h.崔德崔德华 DH Chui DH ChuiLithium blocks Ab accumulation崔德崔德华 DH Chui DH Chui崔德华 DH ChuiEffectsofGSK-3EffectsofGSK-3 onADonADGSK-3 oA NFT formationNeuronal lossSynapse lossMemory lossAktkinesinTau accumulationGSK-3GSK-3 Inhibitor InhibitortauThis suggests that inhibiting GSK-3 is a promising AD therapyp53Axonal transportdegradation崔德崔德华 DH Chui DH ChuiEffects of GSK-3b on ADGSK-3boTherapeutic Approach for Alzheimer Disease崔德崔德华 DH Chui DH ChuiTherapeutic Approach for AlzhTherapeutic Approach for Alzheimer Disease1.ADAD的一般护理、经济、法律的一般护理、经济、法律2.2.西医药治疗西医药治疗 胆碱酯酶抑制剂疗法胆碱酯酶抑制剂疗法 ADAD的新免疫疗法的新免疫疗法 抗炎疗法抗炎疗法 gamagama和和beta-APPbeta-APP分泌酶抑制剂疗法分泌酶抑制剂疗法 GSK-3betaGSK-3beta抑制剂疗法抑制剂疗法 其他其他3.3.中医药治疗中医药治疗崔德崔德华 DH Chui DH ChuiTherapeutic Approach for Alzh乙酰胆碱与乙酰胆碱与AD1 1）中枢乙）中枢乙酰胆碱含量下降、胆碱乙胆碱含量下降、胆碱乙酰化化酶（ChATChAT）、胆碱）、胆碱酯酶 （AchEAchE）活性降低或乙）活性降低或乙酰胆碱受体（胆碱受体（M-AchRM-AchR、N-AchRN-AchR）敏感性降低是）敏感性降低是 ADAD的主要病理改的主要病理改变之一。之一。2 2）胆碱能神）胆碱能神经元主要位于元主要位于纹状体、伏隔核、嗅状体、伏隔核、嗅结节、海、海马和皮和皮质2-42-4层崔德崔德华 DH Chui DH Chui乙酰胆碱与AD1）中枢乙酰胆碱含量下降、胆碱乙酰化酶（ChAAcetylcholine a)Ach synthesis b)Ach degradation Tau崔德崔德华 DH Chui DH ChuiAcetylcholine a)Ach synthesisMemory loss-DementiaAlzheimer disease崔德崔德华 DH Chui DH ChuiMemory loss-DementiaAlzheimer胆碱抑制剂与胆碱抑制剂与AD胆碱抑制胆碱抑制剂；安理申（安理申（DonapezilDonapezil，多多奈奈哌齐，商品名，商品名AriceptAricept)艾斯能艾斯能(rivastigminerivastigmine，利凡斯的明，商品名，利凡斯的明，商品名ExelonExelon)加加兰他敏（他敏（galantaminegalantamine，加，加兰他敏，商品名他敏，商品名ReminylReminyl）美金美金刚胺胺 （MemantineMemantine）利用利用药物减物减轻早期早期 AD AD 患者的症状是可能的。到患者的症状是可能的。到 2002 2002 年年 1 1 月，月，FDA FDA 已批准了用于提高已批准了用于提高记忆力和减力和减缓 AD AD 病情病情发展的展的药物。物。乙乙酰胆碱胆碱酯酶的抑制的抑制剂，通，通过抑制中枢突触抑制中枢突触间隙的乙隙的乙酰胆碱胆碱酯酶的活性，阻止乙的活性，阻止乙酰胆碱（胆碱（AchAch）的分解，提高患）的分解，提高患者者脑中中AchAch的水平（的水平（AchAch含量降低是含量降低是ADAD主要病理主要病理变化之一），可以改善早期化之一），可以改善早期ADAD的症状，但并不是的症状，但并不是针对病因的根治。病因的根治。第四种美金第四种美金刚胺胺则是是NMDANMDA受体的拮抗受体的拮抗剂，它不，它不仅可拮抗可拮抗兴奋性氨基酸的性氨基酸的兴奋毒性，毒性，还可以防止可以防止细胞内胞内钙的聚集及的聚集及超超载而造成神而造成神经细胞的胞的损伤和凋亡，和凋亡，应用用NMDANMDA受体低受体低亲和性非和性非竞争拮抗争拮抗剂治治疗痴呆，痴呆，显示了神示了神经保保护和提高胆碱和提高胆碱能功能的作用。能功能的作用。这些些药物已被物已被证实能能够改善改善记忆效果，且副作用更少。效果，且副作用更少。遗憾的是，憾的是，这些些药物并非物并非对每个人都有效，而且其每个人都有效，而且其疗效效仅限于早期和中期限于早期和中期 AD AD 患者。患者。崔德崔德华 DH Chui DH Chui胆碱抑制剂与AD胆碱抑制剂；利用药物减轻早期 AD 患者的症ADAD的新免疫疗法的新免疫疗法AD的新免疫疗法HistoryofpassiveantibodytherapyHistoryofpassiveantibodytherapyIn the early 1890s,Behring and Kitasato found that injecting nonlethal doses of tetanus toxin into animals causes the animals blood to develop the ability to neutralize the toxin in 1901,von Behring was awarded the first Nobel prize in Medicine.崔德崔德华 DH Chui DH ChuiHistory of passive antibody thInflammation and immune mechanisms in Alzheimers diseaseDennis J.Selkoe NATURE VOL 420 19/26 DECEMBER 2002崔德崔德华 DH Chui DH ChuiInflammation and immune mechanThe A Life Cycle and Possible Points of Therapeutic InterventionsTanzi RETanzi RE Cell.2005 25;120 545 Cell.2005 25;120 545 崔德崔德华 DH Chui DH ChuiThe A Life Cycle and PossibleAdaptiveImmunityCNS as a immune privilege site:blood-brain-barrierB cell and T cell epitope:implication for vaccine崔德崔德华 DH Chui DH ChuiAdaptive ImmunityCNS as a immu崔德崔德华 DH Chui DH Chui崔德华 DH Chui崔德崔德华 DH Chui DH Chui崔德华 DH Chui基础医学神经生物学课件神经系统退行性疾病基础基础医学神经生物学课件神经系统退行性疾病基础ImproveAImproveA clearancewhileclearancewhileavoidinginflammatoryeffectavoidinginflammatoryeffect崔德崔德华 DH Chui DH ChuiImprove Ab clearance while 崔德华Western blotConfocal:intensity of CD11b IRWTEP2-/-Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced A Phagocytosis Yet Lack A-activated NeurotoxicityAm J PatholAm J Pathol,Vol.166,No.4,2005崔德崔德华 DH Chui DH ChuiWestern blotConfocal:intensitMicroglia lacking E prostanoid receptor subtype 2 have enhanced A phagocytosis yet lack A-activated neurotoxicityMicrogliacanbeneuroprotectivebyphagocytosingAb;however,thiscomesatthecostofactivatedinnateimmunitythatcausesparacrinedamagetoneurons.AblationofEprostanoidreceptorsubtype2significantlyincreasedmicroglial-mediatedclearanceofAbpeptidesfromADbrainsectionsandsuppressedAb-activatedmicroglia-mediatedparacrineneurotoxicity.Am J PatholAm J Pathol,Vol.166,No.4,2005崔德崔德华 DH Chui DH ChuiMicroglia lacking E prostanoid基础医学神经生物学课件神经系统退行性疾病基础基础医学神经生物学课件神经系统退行性疾病基础基础医学神经生物学课件神经系统退行性疾病基础基础医学神经生物学课件神经系统退行性疾病基础基础医学神经生物学课件神经系统退行性疾病基础谢 谢！上述上述资料不是面向料不是面向临床医床医疗，作，作为教学参考教学参考资料。料。想复制，想复制，请发来来邮件商件商议。谢 谢！