【学习课件】神经系统退行性疾病基础

NeurodegenerativeDiseases 崔德华 DHChui MD PhD 博士生导师 WhatIsNeurodegenerativediseases Hereditaryandsporadicconditionswhicharecharacterizedbyprogressivenervoussystemdysfunction Thesedisordersareoftenassociatedwithatrophy Apoptosis oftheaffectedcentralorperipheralnervoussystemstructures 崔德华DHChui NeurodegenerativeDiseases Alzheimer sDisease AD APP chr21 PS1 chr14 PS2 chr1 ApoE chr19 Parkinson sDisease PD parkingenealph synuclein autosoma Huntington sDisease HD CAGrepead chr4 AmyotrophicLateralSclerosis ALSCreutzfeldt JakobDisease CJD Corticobasaldegeneration CBD Multi infarctDementia MID LewyBodyDiseases LBD Multiplesystematrophy MSA Progressivesupranuclearpalsy PSP Pick sDiseaseHeredodegenerativeDisorders ParaneoplasticSyndromes OlivopontocerebellarAtrophiesPostpoliomyelitisSyndrome 崔德华DHChui 大脑皮层变性 包括Alzheimer病 Pick病 Creutzfeldt Jakob病 海绵状变性 等 锥体外系统变性 包括Huntington病 Hallervorden Spatz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 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 Machado Joseph病等 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 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 自主神经系统变性 包括Riley Day症候群 全自主神经功能不全 Shy Drager症候群等 多系统变性 MSA 包括上述1 2 3 6等的混合类型 NeurodegenerativeDiseasesClassification 崔德华DHChui Parkinsondisease 崔德华DHChui 崔德华DHChui WhatIsAlzheimerDisease TheMolecularMechanismsofAlzheimerDisease TherapeuticApproachforAlzheimerDisease 崔德华DHChui AlzheimerDisease 奥古斯特 51 崔德华DHChui GrowthinU S PopulationAged65 75 and85 Source U S CensusBureau 崔德华DHChui GenesAssociatedwithAlzheimerDisease 崔德华DHChui ClassificationofSenileDementia DSM IV分类1 阿尔茨海默病 AD 2 血管性痴呆 CVD 3 脑外伤所致痴呆4 Parkinson病所致痴呆5 Huntington病所致痴呆6 HIV病所致痴呆7 Pick病所致痴呆8 Creutzfeldt Jacob病所致痴呆9 物质和躯体病所致痴呆10 其它痴呆 Lewybodydementia 崔德华DHChui TheADdiagnosis AD临床诊断的权威标准主要有3个 世界卫生组织的疾病国际分类第10版 internationalclassificationofdiseases 10threvision ICD 10 中的标准 美国国立神经 语言疾病和卒中研究所 TheNationalInstituteofNeurologicalandCommunicativeDisorders NINCDS 与AD及相关疾病协会 TheAlzheimer sDiseaseandRelatedDisordersAssociation ADRDA 制定的标准 美国精神病诊断和统计手册修订第4版 theDiagnosticandStatisticalManualofMentalDisorders 4thedition 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 ProbableAD 可能AD PossibleAD 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 崔德华DHChui ADclinicalsymptom 神经症状和体征 认知性症状 记忆 非认知性症状 精神和行为症状 失用 失认 失语 执行功能 崔德华DHChui 崔德华DHChui CommercialBiomarkerKitsforDiagnosisAD 崔德华DHChui 崔德华DHChui 崔德华DHChui HowDiscriminationBetweenEarlierPeriodADandAge AssociatedMemoryImpairmentinAging 崔德华DHChui 1986年美国国立精神保健研究所提出 AAMIAge AssociatedMemoryImpairment 随年龄增加出现非病理性的记忆力下降 健忘是老年人脑功能衰弱的表现 痴呆则是病理性的脑器质性智能衰退 崔德华DHChui 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 而痴呆则是病理性的脑器质性智能衰退 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 崔德华DHChui 90y 崔德华DHChui Nostatisticallysignificantdifferencesinthetotalnumberofneuronswereobservedinthenon dementedgroup TheJournalofNeuroscience July15 1996 16 14 4491 4500 崔德华DHChui ProfoundLossofEntorhinalCortexNeuronsOccursinVeryMildAlzheimerDisease TheJournalofNeuroscience July15 1996 16 14 4491 4500 ThenumberofneuronsintheECintheADgroup n 10 comparedwithCDR50controls n 10 correlatedwiththeclinicalseverityofdementia Thedifferenceincreasedfrom32 intheCDR 0 5subgroup n 4 to69 intheCDR 3subgroup n 5 崔德华DHChui SchematicrepresentationofregionalandlaminarNFTformationandneuronallossinnormalagingandAD SCIENCEVOL 278 412 419 1997 NFT densitiestheyellowflame shapedstructuresrepresentasemiquantitative EC entorhinalcortex SP stratumpyramidaleoftheCA1field ITC inferiortemporalcortex SFC superiorfrontalcortex 崔德华DHChui WhatisPairedHelicalFilamentsTau PHFTau 崔德华DHChui a Thecytoskeletonb componentsofthecytoskeleton 崔德华DHChui Sulfo glycosaminoglycancontentaffectsPHF tausolubilityandallowstheidentificationofdifferenttypesofPHFs 崔德华DHChui 崔德华DHChui 崔德华DHChui APP Amyloidprecursorprotein 崔德华DHChui WhatisPresenilin APPandAb 崔德华DHChui MolecularfeaturesofpresenilinandAPP 崔德华DHChui MolecularfeaturesofAPPandAbpeptides APP Amyloidprecursorprotein 崔德华DHChui presenilin Psn APP secretase A Presenilincomplex 崔德华DHChui Aggregationof amyloidisamultistepprocess 崔德华DHChui Courtesy Prof C Glabe UCIrvine 崔德华DHChui Proposedactionsofheatshockprotein70andheatshockprotein40chaperonesonamyloidassembly NATUREREVIEWS NEUROSCIENCEVOLUME6 JANUARY2005 15 崔德华DHChui Directandindirecteffectsofmolecularchaperonesondiseaseproteintoxicity NATUREREVIEWS NEUROSCIENCEVOLUME6 JANUARY2005 15 崔德华DHChui Proteinmisfoldingdiseasesassociatedwithmolecularchaperones NATUREREVIEWS NEUROSCIENCEVOLUME6 JANUARY2005 15 崔德华DHChui PresenilinAbcascadesinAD 崔德华DHChui Transgenicmicewithpresenilin1mutations hPS1 FVB Nmice Microinjectionmethod FVB Nmice2 pAxCAwt vector3 h PDGFpromoter4 hPS1 L286V cDNAhPS1 H163R cDNA Chui DH etal NatMed5 560 4 1999 崔德华DHChui DarkneuroncountsaresignificantlyhigherrinagedPS1mutantmicewithoutamyloidplaqueformation Chui DH etal NatMed5 560 4 1999 崔德华DHChui NeuronswithintracellularAb positivedeposits Chui D H etal NatMed5 560 4 1999 崔德华DHChui AnalysisofapoptosisbydoublestainingwithAb42 green andTUNEL red PS1FAD iAb42 negative TUNEL iAb42 positive TUNEL Mean SEM 0 05 0 10 0 00 Chuietal JAlzheimersDis 2001Apr 3 2 231 239 Chui DH etal JofAlzheimerDisease 2001 3 231 崔德华DHChui ImpairmentofLTPinbrainof3xTG 崔德华DHChui Ab Amyloidaggregations Senileplaques PHF Tau Neuronaldeath APP Ab Alzheimerdisease Dementia HypothesisofAmyloidCascade ExtracelluarAb PS 1mutation PathogenicroleofthePS 1mutationisUpstreamofamyloidcascade EnhancedproductionofAb42 IntracellularAb42 Neuronaldegeneration Alzheimerdisease Dementia 崔德华DHChui Summary 1 Mutationsofpresenilin1 PS 1 enhancethegenerationofAb1 42 indicatingthatPS 1isinvolvedinamyloidogenesis WefirstlyfoundthatneurodegenerationwassignificantlyacceleratedinolderagedmicewithmutantPS 1 withoutamyloidplaqueformation ThereweresignificantlymoreneuronscontainingintracellularlydepositedAb42inagedmutanttransgenicmice PathogenicroleofthePS 1mutationisUpstreamofamyloidcascade 崔德华DHChui FormationofTAUinclusionsinknock inmicewithfamilialAlzheimer sdisease FAD mutationofpresenilin1 PS1 Tanemura Chuietal JBC 2005 崔德华DHChui ImmunostainingwithPS1andPHF tau Chuietal JNeurosciRes 1998 1 53 1 99 PS1 N AT 8 PS1 C AT 8 崔德华DHChui tau ins tau sol PS199 PS262 PS396 PS404 PS422 AT8 Tau 1 wPS1 mPS1 hetero mPS1 homo wPS1 mPS1 hetero mPS1 homo WesternblotsofSDS insolubleandRIPA solublematerials Tanemura Chuietal JBC 2005 崔德华DHChui Tanemura Chuietal JBC 2005 TheformationandaccumulationoffilamentoustauwereAcceleratedbyactivatingGSk 3bn GSK 3b GSK 3b Ser 9 WesternblotofGSK 3b wPS1 mPS1 hetero mPS1 homo 16000 14000 12000 10000 8000 6000 wild hetero homo Relativeactivity cpm mgprotein min GSk 3bActivity 崔德华DHChui Summary 2 PS1mutationscontributetotheonsetofADnotonlybyenhancingA 1 42productionbutbyalsoacceleratingtheformationandaccumulationoffilamentoustau Tanemura Chuietal JBC 2005 崔德华DHChui PS1mayactasamoleculartether connectingGSK 3 withimportantsubstrates P53 崔德华DHChui J Biol Chem Vol 278 Issue49 48872 48879 Domainsofp53thatregulateitsassociationwithGSK3b 崔德华DHChui NeuronalDegeneration Activatesp53Promoter IntracellularAb42 崔德华DHChui RT PCRAnalysesofp53mRNAinAPP Tg 3M 6Mand10M Oyagi Asahara Chuietal FASEBJ 2005 崔德华DHChui Immunoblottinganalysis immunocytochemicalstaininganddoubleimmunostaininginADbrain Oyagi Asahara Chuietal FASEBJ 2005 崔德华DHChui Summary 3 IntracellularA 42directlyactivatedthep53promoterresultinginp53 dependentapoptosis Remarkably accumulationofbothA 42andp53wasfoundinsomedegenerating shapeneuronsinbothmiceandADcases Thus theintracellularA 42 p53pathwaymaybedirectlyrelevanttoneuronallossinAD IntracellularA 42maycausep53 dependentneuronalapoptosisthroughactivationofthep53promoter thusdemonstratinganalternativepathogenesisinAD Oyagi Asahara Chuietal FASEBJ 2005 崔德华DHChui StructureofHumanGSK3 崔德华DHChui GSK 3aisrequiredforAbproduction CHO APP695cellsweretransfectedwithGFPorGSK 3a andsecretedAb42 崔德华DHChui LithiumblocksAbaccumulationinculturedneuronsandinthebrainsofmiceoverproducingAbpeptides EmbryoniccorticalneuronswereinfectedwithSFVcontainingwild typeAPP APP WT orAPP Swedish KM670 671NL thentreatedwithLiClfor24h 崔德华DHChui 崔德华DHChui EffectsofGSK 3bonAD GSK 3b oAb NFTformation Neuronalloss Synapseloss Memoryloss Akt kinesin Tauaccumulation GSK 3 Inhibitor tau ThissuggeststhatinhibitingGSK 3 isapromisingADtherapy p53 Axonaltransportdegradation 崔德华DHChui TherapeuticApproachforAlzheimerDisease 崔德华DHChui TherapeuticApproachforAlzheimerDisease 1 AD的一般护理 经济 法律2 西医药治疗胆碱酯酶抑制剂疗法AD的新免疫疗法抗炎疗法gama和beta APP分泌酶抑制剂疗法GSK 3beta抑制剂疗法其他3 中医药治疗 崔德华DHChui 乙酰胆碱与AD 1 中枢乙酰胆碱含量下降 胆碱乙酰化酶 ChAT 胆碱酯酶 AchE 活性降低或乙酰胆碱受体 M AchR N AchR 敏感性降低是AD的主要病理改变之一 2 胆碱能神经元主要位于纹状体 伏隔核 嗅结节 海马和皮质2 4层 崔德华DHChui Acetylcholinea Achsynthesisb Achdegradation Tau 崔德华DHChui Memoryloss Dementia Alzheimerdisease 崔德华DHChui 胆碱抑制剂与AD 胆碱抑制剂 安理申 Donapezil 多奈哌齐 商品名Aricept 艾斯能 rivastigmine 利凡斯的明 商品名Exelon 加兰他敏 galantamine 加兰他敏 商品名Reminyl 美金刚胺 Memantine 利用药物减轻早期AD患者的症状是可能的 到2002年1月 FDA已批准了用于提高记忆力和减缓AD病情发展的药物 乙酰胆碱酯酶的抑制剂 通过抑制中枢突触间隙的乙酰胆碱酯酶的活性 阻止乙酰胆碱 Ach 的分解 提高患者脑中Ach的水平 Ach含量降低是AD主要病理变化之一 可以改善早期AD的症状 但并不是针对病因的根治 第四种美金刚胺则是NMDA受体的拮抗剂 它不仅可拮抗兴奋性氨基酸的兴奋毒性 还可以防止细胞内钙的聚集及超载而造成神经细胞的损伤和凋亡 应用NMDA受体低亲和性非竞争拮抗剂治疗痴呆 显示了神经保护和提高胆碱能功能的作用 这些药物已被证实能够改善记忆效果 且副作用更少 遗憾的是 这些药物并非对每个人都有效 而且其疗效仅限于早期和中期AD患者 崔德华DHChui AD的新免疫疗法 Historyofpassiveantibodytherapy Intheearly1890s BehringandKitasatofoundthatinjectingnonlethaldosesoftetanustoxinintoanimalscausestheanimals bloodtodeveloptheabilitytoneutralizethetoxin in1901 vonBehringwasawardedthefirstNobelprizeinMedicine 崔德华DHC