基础医学神经生物学课件神经系统退行性疾病基础.ppt
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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,Neurodegenerative Diseases崔德华,What Is Neurodegenerative diseases,Hereditary and sporadic conditions which are characterized by progressive nervous system dysfu
2、nction. These disorders are often associated with atrophy (Apoptosis) of the affected central or peripheral nervous system structures.,崔德华 DH Chui,What Is Neurodegenerative dise,Neurodegenerative Diseases,Alzheimers Disease (AD) APP (chr 21) PS1 (chr 14 )PS2 (chr 1 )ApoE (chr 19) Parkinsons Disease
3、(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
4、) Picks DiseaseHeredodegenerative Disorders,Paraneoplastic Syndromes, Olivopontocerebellar AtrophiesPostpoliomyelitis Syndrome,崔德华 DH Chui,Neurodegenerative DiseasesAlzh,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
5、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
6、。,Neurodegenerative DiseasesClassification,崔德华 DH Chui,大脑皮层变性:包括Alzheimer病、Pick病、Creu,Parkinson disease,崔德华 DH Chui,Parkinson disease崔德华 DH Chui,崔德华 DH Chui,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,Wh
7、at Is Alzheimer Disease ? T,Alzheimer Disease,奥古斯特 (51),崔德华 DH Chui,Alzheimer Disease奥古斯特 (51)崔德华,Growth in U.S. Population Aged 65+, 75+, and 85+,Source: U.S. Census Bureau,崔德华 DH Chui,Growth in U.S. Population Aged,Genes Associated with Alzheimer Disease,崔德华 DH Chui,Genes Associated with Alzheime,
8、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.物质和躯体病所致痴呆10.其它痴呆(Lewy body dementia),崔德华 DH Chui,Classification of Senile Demen,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
9、)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
10、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,The AD diagnosisAD临床诊断的权威标准主要有,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,AD clinical symptom神经症状和体征认知性症,崔
11、德华 DH Chui,崔德华 DH Chui,Commercial Biomarker Kits for Diagnosis AD,崔德华 DH Chui,AgentRecognize siteCompany sam,崔德华 DH Chui,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,HowDiscrimination Between E,1986年美国国立精神保健
12、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,崔德华 DH Chui,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
13、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,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,90 y,崔德华 DH Chu
14、i,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, 1996, 16(14):4491?4500,崔德华 DH Chui,No statistically significant d,Profound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alz
15、heimer 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
16、the CDR =3 subgroup (n =5).,崔德华 DH Chui,Profound Loss of Entorhinal C,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 semiquantitativeEC: entorhinal co
17、rtex SP : stratum pyramidale of the CA1 field ITC: :inferior temporal cortex SFC: superior frontal cortex,崔德华 DH Chui,Schematic representation of re,What isPaired Helical Filaments Tau? - PHF Tau -,崔德华 DH Chui,What isPaired Helical Filam,a) The cytoskeleton b) components of the cytoskeleton,崔德华 DH C
18、hui,a) The cytoskeleton b) compo,Sulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs,崔德华 DH Chui,Sulfo-glycosaminoglycan conten,崔德华 DH Chui,崔德华 DH Chui,崔德华 DH Chui,崔德华 DH Chui,APP : Amyloid precursor protein,崔德华 DH Chui,APP : Amyloid pr
19、ecursor protei,What is Presenilin, APP and Ab ?,崔德华 DH Chui,What is Presenilin, APP and,Molecular features of presenilin and APP,崔德华 DH Chui,Molecular features of presenil,Molecular features of APP and Ab peptides,APP : Amyloid precursor protein,崔德华 DH Chui,Molecular features of APP and,presenilin (
20、Psn),Ab,APP,secretase,A,Presenilin complex,崔德华 DH Chui,presenilin (Psn)AbAPPsecr,Aggregation of -amyloid is a multi step process,崔德华 DH Chui,Aggregation of -amyloid is a,Courtesy: Prof. C. Glabe, UC Irvine,崔德华 DH Chui,Courtesy: Prof. C. Glabe, UC I,Proposed actions of heat shock protein 70 and heat
21、shock protein 40chaperones on amyloid assembly,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,Proposed actions of heat shock,Direct and indirect effects of molecular chaperones on disease protein toxicity,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,
22、Direct and indirect effects of,Protein misfolding diseases associated with molecular chaperones,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德华 DH Chui,NATURE REVIEWS | NEUROSCIENCE,PresenilinAb cascades in AD,崔德华 DH Chui,PresenilinAb cascades in AD,Transgenic mice with presenilin 1 m
23、utations,hPS1/ FVB/ N mice,Microinjection method,FVB/N mice2) pAxCAwt-vector3) h-PDGF promoter4) hPS1-L286V-cDNA hPS1-H163R-cDNA,Chui, DH. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,Transgenic mice with presenili,Dark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid p
24、laque formation,Chui, DH. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,Dark neuron counts are signifi,Neurons with intracellular Ab-positive deposits,Chui, D.H. et al. Nat Med 5, 560-4. (1999),崔德华 DH Chui,Neurons with intracellular Ab-,Analysis of apoptosis by double staining with Ab42 (green) and TU
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