1、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 What Is Neurodegenerative diseases Hereditary and sporadic conditions which are Hereditary and sporadic conditions which are characterized by progressive nervou
2、s system characterized by progressive nervous system dysfunction.dysfunction.These disorders are often associated with These disorders are often associated with atrophy(Apoptosis)of the affected central or atrophy(Apoptosis)of the affected central or peripheral nervous system structures.peripheral n
3、ervous system structures.崔德华崔德华 DH Chui DH ChuiNeurodegenerative 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
4、)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崔德华崔德华 DH Chui DH Chui1.大脑皮层变性大脑皮
5、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
6、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 崔德华崔德华 DH Chui DH ChuiParkinson disease崔德华崔德华 DH Chui DH Chui崔德华崔德华 DH Chui DH Chui
7、What Is Alzheimer Disease?The Molecular Mechanisms of Alzheimer DiseaseTherapeutic Approach for Alzheimer Disease崔德华崔德华 DH Chui DH ChuiAlzheimer DiseaseThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband.Soon,a rapidly increasing memoryimpairment b
8、ecame evident.She could no longer orient herself in herown dwelling,dragged objects here and there and hid them,and,at timesbelieving that people were out to murder her,started to scream loudly.Alois Alzheimer(1907)奥古斯特奥古斯特 (51)(51)崔德华崔德华 DH Chui DH ChuiGrowth in U.S.Population Aged 65+,75+,and 85+6
9、5+75+85+1900192019401960198019902000202020402050020406080100Source:U.S.Census Bureau崔德华崔德华 DH Chui DH ChuiGenes Associated with Alzheimer DiseaseDiseaseGeneOnsetProductChromosomeEarlyAmyloid precursor protein(APP)21Presenilin 1(PS1)14Presenilin 2(PS2)1LateApolipoprotein E19LDL receptor-related prote
10、in(LRP)122-Macroglobulin(2M)12FE6511Chromosome 12 gene product12distinct from LRP and 2MChromosomal loci10崔德华崔德华 DH Chui DH ChuiClassification 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
11、躯体病所致痴呆10.10.其它痴呆其它痴呆(Lewy body dementia)(Lewy body dementia)崔德华崔德华 DH Chui DH ChuiThe AD diagnosisADAD临床诊断的权威标准主要有临床诊断的权威标准主要有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 Disord
12、ers,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
13、 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。崔德华崔德华 DH Chui DH ChuiAD clinical symptomAD clinical symptom神经症状和体征神经症状和体征认认知性症知性症状状记忆记忆非非认知性症状认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华崔德华 DH Chui DH Chui 崔德华崔德华 DH Chui DH ChuiAgentAgentRecognize Recognize sitesiteCompanyCompany samplesample Det
14、ect 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-L
15、iPA 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崔德华崔德华 DH Chui DH ChuiThe first noticeable symptoms
16、of the illness of this 51-year old womanwas suspiciousness of her husband.Soon,a rapidly increasing memoryimpairment became evident.She could no longer orient herself in herown dwelling,dragged objects here and there and hid them,and,at timesbelieving that people were out to murder her,started to sc
17、ream loudly.Alois Alzheimer(1907)崔德华崔德华 DH Chui DH Chui崔德华崔德华 DH Chui DH ChuiHowDiscrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging崔德华崔德华 DH Chui DH Chui 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 Impairmentmpairm
18、ent 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 健忘是老年人脑功能衰弱的表现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痴呆则是病理性的脑器质性智能衰退。崔德华崔德华 DH Chui DH Chui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
19、；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。崔德华崔德华 DH Chui DH Chui90 y9
20、0 y崔德华崔德华 DH Chui DH ChuiNo statistically significant differences in the total number of neurons were observed in the non-demented group The Journal of Neuroscience,July 15,1996,16(14):4491?4500崔德华崔德华 DH Chui DH Chui Profound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer DiseaseThe
21、 Journal of Neuroscience,July 15,1996,16(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).崔德华崔德华 DH C
22、hui DH ChuiSchematic representation of regional and laminar NFT formation and neuronal loss in normal aging and ADSCIENCE VOL.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
23、 cortex SFC:superior frontal cortex崔德华崔德华 DH Chui DH ChuiWhat isWhat isP Paired aired HHelical elical F Filaments ilaments TauTau？-PHF Tau -崔德华崔德华 DH Chui DH Chuia)The cytoskeleton b)components of the cytoskeleton崔德华崔德华 DH Chui DH ChuiSulfo-glycosaminoglycan content affects PHF-tau solubility and al
24、lows the identification of different types of PHFs崔德华崔德华 DH Chui DH Chui崔德华崔德华 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband.Soon,a rapidly increasing memoryimpairment became evident.She could no longer orient herself in herown
25、 dwelling,dragged objects here and there and hid them,and,at timesbelieving that people were out to murder her,started to scream loudly.Alois Alzheimer(1907)崔德华崔德华 DH Chui DH Chui#APP:Amyloid precursor proteinAPP:Amyloid precursor protein崔德华崔德华 DH Chui DH ChuiWhat is Presenilin,APP and Ab?b?崔德华崔德华 D
26、H Chui DH ChuiMolecular features of presenilin and APP崔德华崔德华 DH Chui DH ChuiMolecular features of APP and Ab peptidesAPP:Amyloid precursor protein崔德华崔德华 DH Chui DH Chuipresenilin(Psn）Ab bAPP secretaseAAPresenilin complex崔德华崔德华 DH Chui DH ChuiAggregation of b b-amyloid is a multi step process崔德华崔德华 D
27、H Chui DH ChuiCourtesy:Prof.C.Glabe,UC Irvine崔德华崔德华 DH Chui DH ChuiProposed actions of heat shock protein 70 and heat shock protein 40chaperones on amyloid assemblyNATURE REVIEWS|NEUROSCIENCE VOLUME 6|JANUARY 2005|15崔德华崔德华 DH Chui DH ChuiDirect and indirect effects of molecular chaperones on disease
28、 protein toxicityNATURE REVIEWS|NEUROSCIENCE VOLUME 6|JANUARY 2005|15崔德华崔德华 DH Chui DH ChuiProtein misfolding diseases associated with molecular chaperonesNATURE REVIEWS|NEUROSCIENCE VOLUME 6|JANUARY 2005|15崔德华崔德华 DH Chui DH Chui PresenilinAb b cascades in AD 崔德华崔德华 DH Chui DH ChuiTransgenic mice wi
29、th 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.et al.Nat Med 5,560-4.(1999)崔德华崔德华 DH Chui DH ChuiDark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid plaque for
30、mationChui,DH.et al.Nat Med 5 5,560-4.(1999)崔德华崔德华 DH Chui DH ChuiNeurons with intracellular Ab b-positive deposits Chui,D.H.et al.Nat Med 5,560-4.(1999)崔德华崔德华 DH Chui DH Chui iAbbnegative /TUNEL+iAbbpositive /TUNEL+Mean,SEM*T h e firs t n o tic e a b le s y m p to m s o f th e illn e s s o f th is
31、5 1-y e a r o ld w o m a nw a s s u s p ic io u s n e s s o f h e r h u s b a n d.S o o n,a ra p id ly in c re a s in g m e m o ryim p a irm e n t b e c a m e e v id e n t.S h e c o u ld n o lo n g e r o rie n t h e rs e lf in h e ro w n d w e llin g,d ra g g e d o b je c ts h e re a n d th e re a n
32、 d h id th e m,a n d,a t tim e sb e lie v in g th a t p e o p le w e re o u t to m u rd e r h e r,s ta rte d to s c re a m lo u d ly.A lo is A lz h e im e r(1 9 0 7)Chui et al,J Alzheimers Dis.2001 Apr;3(2):231-239 Chui,DH.et al.J of Alzheimer Disease.2001;3:231 崔德华崔德华 DH Chui DH Chui Impairment of
33、LTP in brain of 3 x TG The first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband.Soon,a rapidly increasing memoryimpairment became evident.She could no longer orient herself in herown dwelling,dragged objects here and there and hid them,and,at timesbelie
34、ving that people were out to murder her,started to scream loudly.Alois Alzheimer(1907)崔德华崔德华 DH Chui DH ChuiA Ab bAmyloid aggregationsSenile plaquesPHF-TauPHF-TauNeuronal deathAPPA Ab bAlzheimer disease DementiaDementiaHypothesis of Amyloid CascadeExtracelluar AbPathogenic role of the PS-1 mutation
35、is Up stream of amyloid cascadeEnhanced production of Ab42Intracellular Ab42 Neuronal degenerationAlzheimer disease DementiaDementia崔德华崔德华 DH Chui DH ChuiSummary (1)(1)1.Mutations of presenilin 1(PS-1)enhance the generation of Ab1Ab1-42,indicating that PS-1 is involved in amyloidogenesis.2.We firstl
36、y 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 AbAb in aged mutant transgenic mice.Pathogenic role of the PS-1 mutation is Up stream of amyl
37、oid cascade。崔德华崔德华 DH Chui DH ChuiFormation 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崔德华崔德华 DH Chui DH ChuiImmunostaining with PS1 and PHF-tauChui et al.J Neurosci Res.1998,1;53(1):99 C
38、hui et al.J Neurosci Res.1998,1;53(1):99 The first noticeable sym ptom s of the illness of this 51-year old w om anw as suspiciousness of her husband.S oon,a rapidly increasing m em oryim pairm ent becam e evident.S he could no longer orient herself in herow n dw elling,dragged objects here and ther
39、e and hid them,and,at tim esbelieving that people w ere out to m urder her,started to scream loudly.A lois A lzheim er(1907)PS1-NAT-8PS1-C AT-8崔德华崔德华 DH Chui DH Chuitau(ins.)tau(sol.)PS199PS262PS396PS404PS422AT8Tau-1wPS1mPS1(hetero)mPS1(homo)wPS1mPS1(hetero)mPS1(homo)Western blots of SDS-insoluble a
40、nd RIPA-soluble materialsTanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005崔德华崔德华 DH Chui DH ChuiTanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005The formation and accumulation of filamentous tau were Accelerated Accelerated by activating GSk-3by activating GSk-3b b n n The f i r st not i
41、 ceabl e sympt oms of t he i l l ness of t hi s 51-year ol d womanwas suspi ci ousness of her husband.Soon,a r api dl y i ncr easi ng memor yi mpai r ment became evi dent.She coul d no l onger or i ent her sel f i n herown dwel l i ng,dr agged obj ect s her e and t her e and hi d t hem,and,at t i me
42、sbel i evi ng t hat peopl e wer e out t o mur der her,st ar t ed t o scr eam l oudl y.Al oi s Al zhei mer (1907)GSK-3b bGSK-3b b(Ser-9)Western blot of GSK-3b bwPS1mPS1(hetero)mPS1(homo)1600014000120001000080006000wildheterohomoRelative activity(cpm/mg protein/min)GSk-3b b Activity崔德华崔德华 DH Chui DH C
43、huiSummary (2 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
44、filamentous tau.filamentous tau.TanemuraTanemura，Chui et al.JBC,2005Chui et al.JBC,2005崔德华崔德华 DH Chui DH ChuiPS1 may act as a molecular tether,connecting GSK-3 with important substrates.PS1GSK-3PS1TauTauPS1-cateninPS1 AbPhosphorylationof tauNFT Cell death Inhibition ofprotein synthesisGSK-3GSK-3GSK-
45、3-cateninA42 productionP53？崔德华崔德华 DH Chui DH ChuiJ.Biol.Chem.,Vol.278,Issue 49,48872-48879Domains of p53 that regulate its association with GSK3b b崔德华崔德华 DH Chui DH ChuiNeuronal Degeneration Activates p53 Promoter？Intracellular Ab b42崔德华崔德华 DH Chui DH Chui RT-PCR Analyses of p53 mRNA in APP-Tg(3M,6M
46、 and 10M)Oyagi,Asahara,Chui et al.FASEB J.2005Oyagi,Asahara,Chui et al.FASEB J.2005崔德华崔德华 DH Chui DH Chui Immunoblotting analysis,immunocytochemical staining and double immunostaining in AD brainThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband.S
47、oon,a rapidly increasing memoryimpairment became evident.She could no longer orient herself in herown dwelling,dragged objects here and there and hid them,and,at timesbelieving that people were out to murder her,started to scream loudly.Alois Alzheimer(1907)Oyagi,Asahara,Chui et al.FASEB J.2005Oyagi
48、,Asahara,Chui et al.FASEB J.2005崔德华崔德华 DH Chui DH ChuiSummary(3)1.Intracellular Ab b42 directly activated the p53 promoter resulting in p53-dependent apoptosis.2.Remarkably,accumulation of both Ab b42 and p53 was found in some degenerating-shape neurons in both mice and AD cases.3.Thus,the intracell
49、ular Ab b42/p53 pathway may be directly relevant to neuronal loss in AD.Oyagi,Asahara,Chui et al.FASEB J.2005Oyagi,Asahara,Chui et al.FASEB J.2005崔德华崔德华 DH Chui DH ChuiQuickTime遣蓃蒮蒊 闘恚蓈社蒓赦赡菣潜敲蓅蒒蒨缮蔷濠侨菫墙菂钦颣髒黔菑臖Structure of Human GSK3 崔德华崔德华 DH Chui DH ChuiGSK-3a a is required for Ab b productionCHO-AP
50、P695 cells were transfected with GFP or GSK-3a,and secreted Ab42 崔德华崔德华 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband.Soon,a rapidly increasing memoryimpairment became evident.She could no longer orient herself in herown dwelli
