神经系统退行性疾病基础.ppt_文客久久网wenke99.com

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1、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: ,What Is Neurodegenerative diseases,Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorde

2、rs are often associated with atrophy (Apoptosis) of the affected central or peripheral nervous system structures.,崔德华 DH Chui,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) Huntingto

3、ns 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,Paraneop

4、lastic Syndromes, Olivopontocerebellar AtrophiesPostpoliomyelitis Syndrome,崔德华 DH Chui,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、

5、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 DiseasesClassification,崔德华 DH Chui,Parkinson disease,崔德华 DH Chu

6、i,崔德华 DH Chui,What Is Alzheimer Disease ?,The Molecular Mechanisms of Alzheimer Disease,Therapeutic Approach for Alzheimer Disease,崔德华 DH Chui,Alzheimer Disease,奥古斯特 (51),崔德华 DH Chui,Growth in U.S. Population Aged 65+, 75+, and 85+,Source: U.S. Census Bureau,崔德华 DH Chui,Genes Associated with Alzheim

7、er Disease,崔德华 DH Chui,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,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 clas

8、sification 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 Disorder

9、s, 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,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,崔德华 DH Chui,Commer

10、cial Biomarker Kits for Diagnosis AD,崔德华 DH Chui,崔德华 DH Chui,崔德华 DH Chui,HowDiscrimination 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: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,如何区分

11、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

12、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,90 y,崔德华 DH Chui,No statistically significant differences in the total number of neurons were observed in the non-demented group,The Journal of Neuroscience, July 15, 199

13、6, 16(14):4491?4500,崔德华 DH Chui,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

14、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,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 f

15、lame-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 Chui,What isPaired Helical Filaments Tau？ - PHF Tau -,崔德华 DH Chui,a) The cytoskeleton b) components of the cytoskeleton

16、,崔德华 DH Chui,Sulfo-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 Chui,APP : Amyloid precursor protein,崔德华 DH Chui,What is Presenilin, APP and Ab ?,崔德华 DH Chui,Molecular features of presenilin and APP,崔德华 D

17、H Chui,Molecular features of APP and Ab peptides,APP : Amyloid precursor protein,崔德华 DH Chui,presenilin (Psn）,APP,secretase,A,Presenilin complex,崔德华 DH Chui,Aggregation of -amyloid is a multi step process,崔德华 DH Chui,Courtesy: Prof. C. Glabe, UC Irvine,崔德华 DH Chui,Proposed actions of heat shock prot

19、ing diseases associated with molecular chaperones,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,PresenilinAb cascades in AD,崔德华 DH Chui,Transgenic mice with presenilin 1 mutations,hPS1/ FVB/ N mice,Microinjection method,FVB/N mice2) pAxCAwt-vector3) h-PDGF promoter4) hPS1-L2

20、86V-cDNA hPS1-H163R-cDNA,Chui, DH. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,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,Neurons with intracellular Ab-positive deposits,Chui, D.H. et al.

21、 Nat Med 5, 560-4. (1999),崔德华 DH Chui,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:

22、231,崔德华 DH Chui,Impairment of LTP in brain of 3 x TG,崔德华 DH Chui,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 p

23、roduction of Ab42,Intracellular Ab42,Neuronal degeneration,Alzheimer disease,Dementia,崔德华 DH Chui,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 i

24、n 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,Formation of TAU inclusions in knock-

25、in mice with familial Alzheimers disease (FAD) mutation of presenilin 1(PS1),Tanemura，Chui et al. JBC,2005,崔德华 DH Chui,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,tau(ins.),tau(sol.),PS199,PS262,PS396,PS404,PS422,AT8,Tau-1,wPS1,m

26、PS1 (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,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),Wes

27、tern 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,Summary (2),PS1 mutations contribute to the onset of AD not only by enhancing A1-42 production but by also accelerating the formati

28、on and accumulation of filamentous tau.,Tanemura，Chui et al. JBC,2005,崔德华 DH Chui,PS1 may act as a molecular tether, connecting GSK-3 with important substrates.,P53,？,崔德华 DH Chui,J. Biol. Chem., Vol. 278, Issue 49, 48872-48879,Domains of p53 that regulate its association with GSK3b,崔德华 DH Chui,Neuro

29、nal Degeneration,Activates p53 Promoter ？,Intracellular Ab42,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 brain,Oyagi, Asahara, Chui et al.

30、 FASEB J. 2005,崔德华 DH Chui,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 direct

31、ly 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,Structure of Human GSK3,崔德华 DH Chui,GSK-3a is required

32、for Ab production,CHO-APP695 cells were transfected with GFP or GSK-3a, and secreted Ab42,崔德华 DH Chui,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-Swed

33、ish (KM670/671NL), then treated with LiCl for 24 h.,崔德华 DH Chui,崔德华 DH Chui,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 transportdegra

34、dation,崔德华 DH Chui,Therapeutic Approach for Alzheimer Disease,崔德华 DH Chui,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,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

35、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,Acetylcholine a) Ach synthesis b) Ach degradation,Tau,崔德华 DH Chui,Memory loss-Dementia,Alzheimer 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（Meman

36、tine）,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

37、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,AD的新免疫疗法,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 B

38、ehring was awarded the first Nobel prize in Medicine.,崔德华 DH Chui,Inflammation and immune mechanisms in Alzheimers disease,Dennis J. Selkoe NATURE VOL 420 19/26 DECEMBER 2002,崔德华 DH Chui,The A Life Cycle and Possible Points of Therapeutic Interventions,Tanzi RE Cell. 2005 25;120 545,崔德华 DH Chui,Adap

39、tive Immunity,CNS as a immune privilege site: blood-brain-barrierB cell and T cell epitope: implication for vaccine,崔德华 DH Chui,崔德华 DH Chui,崔德华 DH Chui,Improve Ab clearance while avoiding inflammatory effect,崔德华 DH Chui,Western blot,Confocal: intensity of CD11b IR,WT,EP2-/-,Microglia Lacking E Prost

40、anoid Receptor Subtype 2 Have Enhanced Ab Phagocytosis Yet Lack Ab-activated Neurotoxicity,Am J Pathol, Vol. 166, No. 4, 2005,崔德华 DH Chui,Microglia lacking E prostanoid receptor subtype 2 have enhanced Ab phagocytosis yet lack Ab-activated neurotoxicity,Microglia can be neuroprotective by phagocytos

41、ing Ab; however, this comes at the cost of activated innate immunity that causes paracrine damage to neurons.Ablation of E prostanoid receptor subtype 2 significantly increased microglial-mediated clearance of Ab peptides from AD brain sections and suppressed Ab-activated microglia-mediated paracrine neurotoxicity.,Am J Pathol, Vol. 166, No. 4, 2005,崔德华 DH Chui,谢谢！,上述资料不是面向临床医疗，作为教学参考资料。想复制，请发来邮件商议。E-mail: ,

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