神经系统退行性疾病基础

Neurodegenerative Diseases崔德华 （ DH Chui, MD, PhD,） 博士生导师 Neuroscience, Research Institute and Dep. Of Neurobiology Peking University , ChinaE-mail: What Is Neurodegenerative diseasesHereditary and sporadic conditions which are characterized by progressive nervous system dysfunction.These disorders are often associated with atrophy (Apoptosis) of the affected central or peripheral nervous system structures.崔德华 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)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 DH Chui1. 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 ：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 ： 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 ： 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 ：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 ： 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 (MSA)： 包括上述 1、 2、 3、 6等的混合类型。Neurodegenerative DiseasesClassification 崔德华 DH ChuiParkinson disease崔德华 DH Chui崔德华 DH ChuiWhat Is Alzheimer Disease ? The Molecular Mechanisms of Alzheimer DiseaseTherapeutic Approach for Alzheimer Disease崔德华 DH ChuiAlzheimer Disease奥古斯特 (51)崔德华 DH ChuiGrowth in U.S. Population Aged 65+, 75+, and 85+Source: U.S. Census Bureau崔德华 DH ChuiGenes Associated with Alzheimer Disease崔德华 DH ChuiClassification of Senile DementiaDSM-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 (Lewy body dementia)崔德华 DH ChuiThe AD diagnosisAD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 (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。崔德华 DH ChuiAD clinical symptom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 DH Chui 崔德华 DH ChuiAgent Recognize site Company sample Detect methodINNOTEST hTau Ag human tau, antigen in CSF Innogenetics, Belgium 25 L CSF ELISA microplate assayINNOTEST PHOSPHO-TAU(181P)tau(181p) Innogenetics, Belgium 75 L CSF ELISA microplate assayINNOTEST - AMYLOID(1-42) human -amyloid1-42(A1-42) Innogenetics, Belgium 25 L CSF ELISA microplate assayINNO-LiPA ApoEapolipoprotein E genotypese2, e3, and e4Innogenetics, Belgium blood line probe assayINNO-BIA AlzBio3 A1-42,total-tau, P-tau181P Innogenetics, Belgium Undiluted (75 L)/CSF bead-based multiparameter immunoassayCommercial Biomarker Kits for Diagnosis AD崔德华 DH Chui崔德华 DH Chui崔德华 DH ChuiHowDiscrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging崔德华 DH Chui 1986年美国国立精神保健研究所提出 :AAMIAge-Associated Memory Impairment 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 DH Chui如何区分老年健忘与早期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 DH Chui90 y崔德华 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 DH Chui Profound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer DiseaseThe Journal of Neuroscience, July 15, 1996, 16(14):4491?4500The 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 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 cortex SFC: superior frontal cortex崔德华 DH ChuiWhat isPaired Helical Filaments Tau？- PHF Tau -崔德华 DH Chuia) The cytoskeleton b) components of the cytoskeleton崔德华 DH ChuiSulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs崔德华 DH Chui崔德华 DH Chui崔德华 DH ChuiAPP : Amyloid precursor protein崔德华 DH ChuiWhat isPresenilin, APP and A ? 崔德华 DH ChuiMolecular features of presenilin and APP崔德华 DH ChuiMolecular features of APP and Ab peptidesAPP : Amyloid precursor protein崔德华 DH Chuipresenilin (Psn）AAPP secretaseAPresenilin complex崔德华 DH ChuiAggregation of -amyloid is a multi step process崔德华 DH ChuiCourtesy: Prof. C. Glabe, UC Irvine崔德华 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 DH ChuiDirect and indirect effects of molecular chaperones on disease protein toxicityNATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15崔德华 DH ChuiProtein misfolding diseases associated with molecular chaperonesNATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15崔德华 DH Chui PresenilinA cascades in AD 崔德华 DH ChuiTransgenic mice with presenilin 1 mutations hPS1/ FVB/ N miceMicroinjection method1) FVB/N mice2) pAxCAwt-vector3) h-PDGF promoter4) hPS1-L286V-cDNAhPS1-H163R-cDNAChui, DH. et al. Nat Med 5, 560-4. (1999)崔德华 DH ChuiDark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid plaque formationChui, DH. et al. Nat Med 5, 560-4. (1999)崔德华 DH ChuiNeurons with intracellular A-positive deposits Chui, D.H. et al. Nat Med 5, 560-4. (1999)崔德华 DH ChuiAnalysis of apoptosis by double staining with A42 (green) and TUNEL (red)PS1 FADiA42negative / TUNEL+ iA42positive / TUNEL+%Mean, SEM0.050.10*0.00Chui 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 DH Chui Impairment of LTP in brain of 3 x TG 崔德华 DH ChuiAAmyloid aggregationsSenile plaquesPHF-TauNeuronal deathAPPAAlzheimer disease DementiaHypothesis of Amyloid CascadeExtracelluar AbPS-1 mutationPathogenic role of the PS-1 mutation is Up stream of amyloid cascadeEnhanced productionof Ab42Intracellular Ab42 Neuronal degenerationAlzheimer disease Dementia崔德华 DH ChuiSummary (1)1. Mutations of presenilin 1 (PS-1) enhance the generation of A1-42, 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 A42 in aged mutant transgenic mice. Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade。崔德华 DH ChuiFormation of TAU inclusions in knock-in mice with familial Alzheimers disease (FAD) mutation of presenilin 1(PS1)Tanemura， Chui et al. JBC,2005崔德华 DH ChuiImmunostaining with PS1 and PHF-tauChui et al. J Neurosci Res. 1998, 1;53(1):99 PS1-NAT-8PS1-C AT-8崔德华 DH Chuitau(ins.)tau(sol.)PS199PS262PS396PS404PS422AT8Tau-1wPS1 mPS1 (hetero) mPS1 (homo) wPS1 mPS1 (hetero) mPS1 (homo)Western blots of SDS-insoluble and RIPA-soluble materialsTanemura， Chui et al. JBC,2005崔德华 DH ChuiTanemura， Chui et al. JBC,2005The formation and accumulation of filamentous tau were Accelerated by activating GSk-3 n GSK-3GSK-3(Ser-9)Western blot of GSK-3wPS1 mPS1 (hetero) mPS1 (homo)1600014000120001000080006000wild hetero homoRelative activity (cpm/mg protein/min)GSk-3 Activity崔德华 DH ChuiSummary (2)PS1 mutations contribute to the onset of AD not only by enhancing A1-42 production but by also accelerating the formation and accumulation of filamentous tau.Tanemura， Chui et al. JBC,2005崔德华 DH ChuiPS1 may act as a molecular tether, connecting GSK-3 with important substrates.PS1GSK-3PS1TauTauPS1-cateninPS1AbPhosphorylationof tauNFTCell death Inhibition ofprotein synthesisGSK-3GSK-3GSK-3-cateninA42 productionP53 ？崔德华 DH ChuiJ. Biol. Chem., Vol. 278, Issue 49, 48872-48879Domains of p53 that regulate its association with GSK3崔德华 DH ChuiNeuronal Degeneration Activates p53 Promoter ？Intracellular A42崔德华 DH Chui RT-PCR Analyses of p53 mRNA in APP-Tg (3M, 6M and 10M)Oyagi, Asahara, Chui et al. FASEB J. 2005 崔德华 DH Chui Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brainOyagi, Asahara, Chui et al. FASEB J. 2005 崔德华 DH ChuiSummary (3)1. Intracellular A42 directly activated the p53 promoter resulting in p53-dependent apoptosis. Remarkably, accumulation of both A42 and p53 was found in some degenerating-shape neurons in both mice and AD cases. Thus, the intracellular A42/p53 pathway may be directly relevant to neuronal loss in AD. 1. Intracellular A42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.Oyagi, Asahara, Chui et al. FASEB J. 2005 崔德华 DH ChuiStructure of Human GSK3 崔德华 DH ChuiGSK-3a is required for A productionCHO-APP695 cells were transfected with GFP or GSK-3a, and secreted Ab42 崔德华 DH ChuiLithium blocks A accumulation in cultured neurons and in the brains of mice overproducing A peptidesEmbryonic cortical neurons were infected with SFV containing wild-type APP (APP-WT) or APP-Swedish (KM670/671NL), then treated with LiCl for 24 h. 崔德华 DH Chui崔德华 DH ChuiEffects of GSK-3 on ADGSK-3oANFT formationNeuronal lossSynapse lossMemory lossAktkinesinTau accumulationGSK-3 InhibitortauThis suggests that inhibiting GSK-3 is a promising AD therapyp53Axonal transportdegradation崔德华 DH ChuiTherapeutic Approach for Alzheimer Disease崔德华 DH ChuiTherapeutic Approach for Alzheimer Disease1. 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 DH Chui乙酰胆碱与 AD1）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 DH ChuiAcetylcholine a) Ach synthesis b) Ach degradation Tau崔德华 DH ChuiMemory loss-DementiaAlzheimer disease崔德华 DH Chui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 DH ChuiAD的新免疫疗法History of passive antibody therapyIn 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 awa