基础医学神经生物学ppt课件神经系统退行性疾病基础

医学课件园 ,Neurodegenerative Diseases,崔德华 （DH Chui, MD, PhD,） 博士生导师,Neuroscience, Research Institute and Dep. Of Neurobiology Peking University , China E-mail: ,医学课件园 ,What Is Neurodegenerative diseases,Hereditary 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 Chui,医学课件园 ,Neurodegenerative Diseases,Alzheimers 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 Disease Heredodegenerative Disorders, Paraneoplastic Syndromes, Olivopontocerebellar Atrophies Postpoliomyelitis Syndrome,崔德华 DH Chui,医学课件园 ,大脑皮层变性：包括Alzheimer病、Pick病、CreutzfeldtJakob病(海绵状变性)等。 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。 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。 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RileyDay症候群(全自主神经功能不全)、ShyDrager症候群等。 多系统变性(MSA)：包括上述1、2、3、6等的混合类型。,Neurodegenerative Diseases Classification,崔德华 DH Chui,医学课件园 ,Parkinson disease,崔德华 DH Chui,医学课件园 ,崔德华 DH Chui,医学课件园 ,What Is Alzheimer Disease ?,The Molecular Mechanisms of Alzheimer Disease,Therapeutic Approach for Alzheimer Disease,崔德华 DH Chui,医学课件园 ,Alzheimer Disease,奥古斯特 (51),崔德华 DH Chui,医学课件园 ,Growth in U.S. Population Aged 65+, 75+, and 85+,Source: U.S. Census Bureau,崔德华 DH Chui,医学课件园 ,Genes Associated with Alzheimer Disease,崔德华 DH Chui,医学课件园 ,Classification of Senile Dementia,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(Lewy body dementia),崔德华 DH Chui,医学课件园 ,The AD diagnosis,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(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 Chui,医学课件园 ,AD 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,医学课件园 ,崔德华 DH Chui,医学课件园 ,Commercial Biomarker Kits for Diagnosis AD,崔德华 DH Chui,医学课件园 ,崔德华 DH Chui,医学课件园 ,崔德华 DH Chui,医学课件园 ,How Discrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging,崔德华 DH Chui,医学课件园 ,1986年美国国立精神保健研究所提出: AAMI Age-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,医学课件园 ,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 Chui,医学课件园 ,90 y,崔德华 DH Chui,医学课件园 ,No 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,医学课件园 ,Profound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer Disease,The 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 DH Chui,医学课件园 ,Schematic representation of regional and laminar NFT formation and neuronal loss in normal aging and AD,SCIENCE VOL. 278,412-419, 1997,NFT: densities the yellow flame-shaped structures represent a semiquantitative EC: entorhinal cortex SP : stratum pyramidale of the CA1 field ITC: :inferior temporal cortex SFC: superior frontal cortex,崔德华 DH Chui,医学课件园 ,What is Paired Helical Filaments Tau？ - PHF Tau -,崔德华 DH Chui,医学课件园 ,a) The cytoskeleton b) components of the cytoskeleton,崔德华 DH Chui,医学课件园 ,Sulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs,崔德华 DH Chui,医学课件园 ,崔德华 DH Chui,医学课件园 ,崔德华 DH Chui,医学课件园 ,APP : Amyloid precursor protein,崔德华 DH Chui,医学课件园 ,What is Presenilin, APP and Ab ?,崔德华 DH Chui,医学课件园 ,Molecular features of presenilin and APP,崔德华 DH Chui,医学课件园 ,Molecular features of APP and Ab peptides,APP : Amyloid precursor protein,崔德华 DH Chui,医学课件园 ,presenilin (Psn）,APP,secretase,A,Presenilin complex,崔德华 DH Chui,医学课件园 ,Aggregation of -amyloid is a multi step process,崔德华 DH Chui,医学课件园 ,Courtesy: Prof. C. Glabe, UC Irvine,崔德华 DH Chui,医学课件园 ,Proposed actions of heat shock protein 70 and heat shock protein 40 chaperones on amyloid assembly,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,医学课件园 ,Direct and indirect effects of molecular chaperones on disease protein toxicity,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,医学课件园 ,Protein misfolding diseases associated with molecular chaperones,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,医学课件园 ,Presenilin Ab cascades in AD,崔德华 DH Chui,医学课件园 ,Transgenic mice with presenilin 1 mutations,hPS1/ FVB/ N mice,Microinjection method,FVB/N mice 2) pAxCAwt-vector 3) h-PDGF promoter 4) hPS1-L286V-cDNA hPS1-H163R-cDNA,Chui, DH. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,医学课件园 ,Dark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid plaque formation,Chui, DH. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,医学课件园 ,Neurons with intracellular Ab-positive deposits,Chui, D.H. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,医学课件园 ,Analysis of apoptosis by double staining with Ab42 (green) and TUNEL (red),PS1 FAD,iAb42-negative / TUNEL+,iAb42-positive / TUNEL+,%,Mean, SEM,0.05,0.10,*,0.00,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 DH Chui,医学课件园 ,Impairment of LTP in brain of 3 x TG,崔德华 DH Chui,医学课件园 ,Ab,Amyloid aggregations,Senile plaques,PHF-Tau,Neuronal death,APP,Ab,Alzheimer disease,Dementia,Hypothesis of Amyloid Cascade,Extracelluar Ab,PS-1 mutation,Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade,Enhanced production of Ab42,Intracellular Ab42,Neuronal degeneration,Alzheimer disease,Dementia,崔德华 DH Chui,医学课件园 ,Summary (1),Mutations of presenilin 1 (PS-1) enhance the generation of Ab1-42, indicating that PS-1 is involved in amyloidogenesis. We firstly found that neurodegeneration was significantly accelerated in older aged mice with mutant PS-1, without amyloid plaque formation. There were significantly more neurons containing intracellularly deposited Ab42 in aged mutant transgenic mice. Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade。,崔德华 DH Chui,医学课件园 ,Formation 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 Chui,医学课件园 ,Immunostaining with PS1 and PHF-tau,Chui et al. J Neurosci Res. 1998, 1;53(1):99,PS1-N,AT-8,PS1-C,AT-8,崔德华 DH Chui,医学课件园 ,tau (ins.),tau (sol.),PS199,PS262,PS396,PS404,PS422,AT8,Tau-1,wPS1,mPS1 (hetero),mPS1 (homo),wPS1,mPS1 (hetero),mPS1 (homo),Western blots of SDS-insoluble and RIPA-soluble materials,Tanemura，Chui et al. JBC,2005,崔德华 DH Chui,医学课件园 ,Tanemura，Chui et al. JBC,2005,The formation and accumulation of filamentous tau were Accelerated by activating GSk-3b n,GSK-3b,GSK-3b (Ser-9),Western blot of GSK-3b,wPS1,mPS1 (hetero),mPS1 (homo),16000,14000,12000,10000,8000,6000,wild,hetero,homo,Relative activity (cpm/mg protein/min),GSk-3b Activity,崔德华 DH Chui,医学课件园 ,Summary (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 Chui,医学课件园 ,PS1 may act as a molecular tether, connecting GSK-3 with important substrates.,P53,？,崔德华 DH Chui,医学课件园 ,J. Biol. Chem., Vol. 278, Issue 49, 48872-48879,Domains of p53 that regulate its association with GSK3b,崔德华 DH Chui,医学课件园 ,Neuronal Degeneration,Activates p53 Promoter ？,Intracellular Ab42,崔德华 DH Chui,医学课件园 ,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,医学课件园 ,Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brain,Oyagi, Asahara, Chui et al. FASEB J. 2005,崔德华 DH Chui,医学课件园 ,Summary (3),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. 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 Chui,医学课件园 ,Structure of Human GSK3,崔德华 DH Chui,医学课件园 ,GSK-3a is required for Ab production,CHO-APP695 cells were transfected with GFP or GSK-3a, and secreted Ab42,崔德华 DH Chui,医学课件园 ,Lithium blocks Ab accumulation in cultured neurons and in the brains of mice overproducing Ab peptides,Embryonic 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,医学课件园 ,崔德华 DH Chui,医学课件园 ,Effects of GSK-3b on AD,GSK-3b,oAb,NFT formation,Neuronal loss,Synapse loss,Memory loss,Akt,kinesin,Tau accumulation,GSK-3 Inhibitor,tau,This suggests that inhibiting GSK-3 is a promising AD therapy,p53,Axonal transport degradation,崔德华 DH Chui,医学课件园 ,Therapeutic Approach for Alzheimer Disease,崔德华 DH Chui,医学课件园 ,Therapeutic Approach for Alzheimer Disease,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 DH Chui,医学课件园 ,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 DH Chui,医学课件园 ,Acetylcholine a) Ach synthesis b) Ach degradation,Tau,崔德华 DH Chui,医学课件园 ,Memory loss-Dementia,Alzheimer disease,崔德华 DH Chui,医学课件园 ,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 Chui,医学课件园 ,AD的新免疫疗法,医学课件园 ,History of passive antibody therapy,In 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.,崔德华 DH Chui,医学课件园 ,Inflammation and immune mechanisms in Alzheimers disease,Dennis J. Selkoe NATURE VOL 420 19/26 DECEMBER 2002,崔德华 DH Chui,医学课件园 ,The A Life Cycle and Possible Points