神經(jīng)系統(tǒng)退行性疾病基礎(chǔ)

1、Neurodegenerative Diseases,崔德華 （DH Chui, MD, PhD,） 博士生導(dǎo)師,Neuroscience, Research Institute and Dep. Of Neurobiology Peking University , China E-mail: dchui@bjmu.edu.cn,What Is Neurodegenerative diseases,Hereditary and

2、 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

3、德華 DH Chui,Neurodegenerative Diseases,Alzheimer‘s Disease (AD) APP (chr 21） PS1 (chr 14 ）PS2 (chr 1 ）ApoE (chr 19） Parkinson's Disease (PD) parkin gene alph-synuclein (autosoma) Huntington's Disease(HD)

4、 CAG repead (chr 4） Amyotrophic Lateral Sclerosis, ALS Creutzfeldt-Jakob Disease(CJD)Corticobasal degeneration (CBD) Multi-infarct Dementia (MID)Lewy Body Diseases (LBD)M

5、ultiple system atrophy (MSA) Progressive supranuclear palsy (PSP) Pick's DiseaseHeredodegenerative Disorders,Paraneoplastic Syndromes, Olivopontocerebellar AtrophiesPostpoliomyelitis Syndrome,崔德華 DH Chui,大腦皮層變性

6、：包括Alzheimer病、Pick病、Creutzfeldt?Jakob病(海綿狀變性)等。錐體外系統(tǒng)變性：包括Huntington病、Hallervorden?Spatz病、Wilson病(肝豆?fàn)詈俗冃?、Seitelberger病(神經(jīng)軸索型營(yíng)養(yǎng)不良)、進(jìn)行性肌陣攣型癲癇。病損在中腦與紋狀體者有Parkinson(帕金森)病、紋狀體黑質(zhì)變性、進(jìn)行性核上型麻痹(PSP)等。腦干小腦變性：包括各種小腦型共濟(jì)失調(diào)、脊髓小腦變性、

7、橄欖?橋腦?小腦變性(OPCA)、Machado?Joseph病等。脊髓變性：包括進(jìn)行性痙攣性截癱、進(jìn)行性后索變性、后側(cè)索聯(lián)合變性、Friedreich共濟(jì)失調(diào)等。運(yùn)動(dòng)系統(tǒng)變性：包括各型運(yùn)動(dòng)神經(jīng)元病，如肌萎縮側(cè)索硬化(ALS)、進(jìn)行性脊髓性肌萎縮(SMA)、進(jìn)行性球麻痹等。自主神經(jīng)系統(tǒng)變性：包括Riley?Day癥候群(全自主神經(jīng)功能不全)、Shy?Drager癥候群等。多系統(tǒng)變性(MSA)：包括上述1、2、3、6等的混

8、合類型。,Neurodegenerative DiseasesClassification,崔德華 DH Chui,Parkinson disease,崔德華 DH Chui,崔德華 DH Chui,What Is Alzheimer Disease ?,The Molecular Mechanisms of Alzheimer Disease,Therapeutic Approach for Alzheimer Disease

9、,崔德華 DH Chui,Alzheimer Disease,奧古斯特 (51),崔德華 DH Chui,Growth in U.S. Population Aged 65+, 75+, and 85+,Source: U.S. Census Bureau,崔德華 DH Chui,Genes Associated with Alzheimer Disease,崔德華 DH Chui,Classification of Senile D

10、ementia,DSM-IV分類1.阿爾茨海默病 (AD)2.血管性癡呆 (CVD)3.腦外傷所致癡呆4.Parkinson病所致癡呆5.Huntington病所致癡呆6.HIV病所致癡呆7.Pick病所致癡呆8.Creutzfeldt-Jacob病所致癡呆9.物質(zhì)和軀體病所致癡呆10.其它癡呆(Lewy body dementia),崔德華 DH Chui,The AD diagnosis,AD臨床

11、診斷的權(quán)威標(biāo)準(zhǔn)主要有3個(gè)：①世界衛(wèi)生組織的疾病國際分類第10版(international classification of diseases, 10th revision, ICD-10)中的標(biāo)準(zhǔn)；②美國國立神經(jīng)、語言疾病和卒中研究所(The National Institute of Neurological and Communicative Disorders, NINCDS)與AD及相關(guān)疾病協(xié)會(huì)(The Alzheimer

12、‘s Disease and Related Disorders Association, ADRDA)制定的標(biāo)準(zhǔn)； ③美國精神病診斷和統(tǒng)計(jì)手冊(cè)修訂第4版(the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Revised, DSM-IV)的標(biāo)準(zhǔn)。 ##上述3個(gè)標(biāo)準(zhǔn)都是當(dāng)前國際公認(rèn)的AD診斷標(biāo)準(zhǔn)，臨床上可根據(jù)需要選擇或互相參

13、照使用。其中美國NINCDS-ADRDA制定的標(biāo)準(zhǔn)中，將AD定義為很可能AD(Probable AD)、可能AD(Possible AD)和確定的AD，操作性較好。應(yīng)用該標(biāo)準(zhǔn)及相關(guān)的診斷量表，AD臨床診斷的準(zhǔn)確率可以提高到90%以上。,崔德華 DH Chui,,AD clinical symptom,神經(jīng)癥狀和體征,,,,,,,認(rèn)知性癥狀,記憶,非認(rèn)知性癥狀,精神和行為癥狀,失用,失認(rèn),失語,執(zhí)行功能,崔德華 DH Chui,,崔德華

14、DH Chui,,Commercial Biomarker Kits for Diagnosis AD,,,,,崔德華 DH Chui,崔德華 DH Chui,,崔德華 DH Chui,HowDiscrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging,崔德華 DH Chui,1986年美國國立精神保健研究所提出:A

15、AMI Age-Associated Memory Impairment @ 隨年齡增加出現(xiàn)非病理性的記憶力下降 @ 健忘是老年人腦功能衰弱的表現(xiàn). @ 癡呆則是病理性的腦器質(zhì)性智能衰退。,崔德華 DH Chui,如何區(qū)分老年健忘與早期AD,健忘是老年人腦功能衰弱的表現(xiàn)，而癡呆則是病理性的腦器質(zhì)性智能衰退，遺忘區(qū)別 健忘的老年人對(duì)做過事情的遺忘總是部分性的； 癡呆的遺忘則是完全惡性的，記不起

16、發(fā)生過的事情，似乎 此事已完全消失。 認(rèn)知能力 健忘老人雖然記憶力下降，但對(duì)時(shí)間、地點(diǎn)、人物關(guān)系和周 圍環(huán)境的認(rèn)知能力絲毫未減； 癡呆老人卻喪失了識(shí)別周圍環(huán)境的認(rèn)知能力，分不清上下午， 不知季節(jié)變化，不知身在何處，有時(shí)甚至找不到回家的路。 生活能力 健忘老人雖會(huì)記錯(cuò)日期有時(shí)前講后忘，但他們?nèi)阅芰侠碜约?的生活，甚至能照顧家人；

17、 癡呆老人隨著病情加重，會(huì)逐漸喪失生活自理能力。 情緒變化 健忘老人有七情六欲； 癡呆老人的情感世界則變得“與世無爭(zhēng)”，麻木不仁。思維變化 健忘老人對(duì)記憶力下降相當(dāng)苦惱，為了不致誤事，常記個(gè)備忘錄； 癡呆老人毫無煩惱，思維越來越遲鈍，言語越來越貧乏，缺乏幽 默感，反應(yīng)遲緩。是否語言豐富，幽默多彩，是區(qū)別生理健忘和癡呆的重要標(biāo)志之一。,崔德華 DH Chui,,,90 y,

18、崔德華 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,,崔德華 DH Chui,,,Profound Loss of E

19、ntorhinal 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)

20、, 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).,崔德華 DH Chui,Schematic representation of regional and laminar NF

21、T 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 : str

22、atum pyramidale of the CA1 field @ ITC: :inferior temporal cortex @ SFC: superior frontal cortex,崔德華 DH Chui,What isPaired Helical Filaments Tau？ - PHF Tau -,崔德華 DH Chui,a) The cytoskeleton b) componen

23、ts of the cytoskeleton,崔德華 DH Chui,Sulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs,崔德華 DH Chui,崔德華 DH Chui,崔德華 DH Chui,APP : Amyloid precursor protein,崔

24、德華 DH Chui,What is Presenilin, APP and Ab ?,崔德華 DH Chui,Molecular features of presenilin and APP,崔德華 DH Chui,Molecular features of APP and Ab peptides,APP : Amyloid precursor protein,崔德華 DH Chui,,,presenilin (Psn）,APP,?

25、??secretase,,,,,Aß,,,Presenilin complex,崔德華 DH Chui,Aggregation of ?-amyloid is a multi step process,崔德華 DH Chui,Courtesy: Prof. C. Glabe, UC Irvine,崔德華 DH Chui,Proposed actions of heat shock protein 70 and heat sh

26、ock protein 40chaperones on amyloid assembly,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德華 DH Chui,Direct and indirect effects of molecular chaperones on disease protein toxicity,NATURE REVIEWS | NEUROS

27、CIENCE VOLUME 6 | JANUARY 2005 | 15,崔德華 DH Chui,Protein misfolding diseases associated with molecular chaperones,NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15,崔德華 DH Chui,PresenilinAb cascades in AD,崔德華 DH

28、Chui,,,,,,,,Transgenic mice with presenilin 1 mutations,,,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 M

29、ed 5, 560-4. (1999),崔德華 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),崔德華 DH Chui,,,,,Neurons with intracellul

30、ar Ab-positive deposits,Chui, D.H. et al. Nat Med 5, 560-4. (1999),崔德華 DH Chui,,,,,Analysis of apoptosis by double staining with Ab42 (green) and TUNEL (red),PS1 FAD,,,iAb42-negative / TUNEL+,iAb42-positive / TUNEL+,%,

31、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,崔德華 DH Chui,,,Impairment of LTP in brain of 3 x TG,崔德華 DH Chui,,,,,,Ab,Amyloid aggrega

32、tions,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,E

33、nhanced production of Ab42,Intracellular Ab42,,,,,Neuronal degeneration,,,Alzheimer disease,Dementia,,崔德華 DH Chui,,,,,Summary (1),Mutations of presenilin 1 (PS-1) enhance the generation of Ab1-42, indicating that PS-1 i

34、s 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 containi

35、ng intracellularly deposited Ab42 in aged mutant transgenic mice. Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade。,崔德華 DH Chui,Formation of TAU inclusions in knock-in mice with familial Alzheimer'

36、;s disease (FAD) mutation of presenilin 1(PS1),Tanemura，Chui et al. JBC,2005,崔德華 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,崔德華 DH Chui,tau(ins.),tau

37、(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,崔德華

38、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),Western blot of GSK-3b,,,,,,,,,,wPS1,mPS1 (hetero),mPS1 (homo),,16000

39、,14000,12000,10000,8000,6000,wild,hetero,homo,Relative activity (cpm/mg protein/min),GSk-3b Activity,崔德華 DH Chui,,,,,Summary (2),PS1 mutations contribute to the onset of AD not only by enhancing Aβ1-42 production but by

40、also accelerating the formation and accumulation of filamentous tau.,Tanemura，Chui et al. JBC,2005,崔德華 DH Chui,PS1 may act as a molecular tether, connecting GSK-3ß with important substrates.,,P53,,,？,崔德華 DH Chui,J.

41、 Biol. Chem., Vol. 278, Issue 49, 48872-48879,Domains of p53 that regulate its association with GSK3b,崔德華 DH Chui,,Neuronal Degeneration,Activates p53 Promoter ？,Intracellular Ab42,崔德華 DH Chui,,,,,RT-PCR Analyses of p53

42、mRNA in APP-Tg (3M, 6M and 10M),,Oyagi, Asahara, Chui et al. FASEB J. 2005,崔德華 DH Chui,,,,,Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brain,Oyagi, Asahara, Chui et al. FASEB J.

43、2005,崔德華 DH Chui,,,,,Summary (3),Intracellular A?42 directly activated the p53 promoter resulting in p53-dependent apoptosis.Remarkably, accumulation of both A?42 and p53 was found in some degenerating-shape neurons in

44、 both mice and AD cases. Thus, the intracellular A?42/p53 pathway may be directly relevant to neuronal loss in AD. Intracellular A?42 may cause p53-dependent neuronal apoptosis through activation of the p53 promote

45、r; thus demonstrating an alternative pathogenesis in AD.,Oyagi, Asahara, Chui et al. FASEB J. 2005,崔德華 DH Chui,Structure of Human GSK3,,,崔德華 DH Chui,GSK-3a is required for Ab production,CHO-APP695 cells

46、were transfected with GFP or GSK-3a, and secreted Ab42,崔德華 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

47、containing wild-type APP (APP-WT) or APP-Swedish (KM670/671NL), then treated with LiCl for 24 h.,崔德華 DH Chui,崔德華 DH Chui,Effects of GSK-3b on AD,GSK-3b,oAb,NFT formation,Neuronal loss,Synapse loss,Memory loss,,,,Akt,,,ki

48、nesin,,,Tau accumulation,,,,,,GSK-3? Inhibitor,,tau,This suggests that inhibiting GSK-3? is a promising AD therapy,p53,,,Axonal transportdegradation,崔德華 DH Chui,Therapeutic Approach for Alzheimer Disease,崔德華 DH Chui,Th

49、erapeutic Approach for Alzheimer Disease,1. AD的一般護(hù)理、經(jīng)濟(jì)、法律2. 西醫(yī)藥治療 膽堿酯酶抑制劑療法 AD的新免疫療法 抗炎療法 gama和beta-APP分泌酶抑制劑療法 GSK-3beta抑制劑療法 其他3.中醫(yī)藥治療,崔德華 DH Chui,乙酰膽堿與AD,,1）中樞乙酰膽堿含量下降、膽堿乙?；福–hAT）、膽

50、堿酯酶 （AchE）活性降低或乙酰膽堿受體（M-AchR、N-AchR）敏感性降低是 AD的主要病理改變之一。2）膽堿能神經(jīng)元主要位于紋狀體、伏隔核、嗅結(jié)節(jié)、海馬和皮質(zhì)2-4層,崔德華 DH Chui,Acetylcholine a) Ach synthesis b) Ach degradation,,Tau,崔德華 DH Chui,Memory loss->Dementia,Alzheimer disease,,崔德華

51、DH Chui,膽堿抑制劑與AD,膽堿抑制劑；安理申（Donapezil，多奈哌齊，商品名Aricept)艾斯能(rivastigmine，利凡斯的明，商品名Exelon)加蘭他敏（galantamine，加蘭他敏，商品名Reminyl）美金剛胺 （Memantine）,利用藥物減輕早期 AD 患者的癥狀是可能的。到 2002 年 1 月，F(xiàn)DA 已批準(zhǔn)了用于提高記憶力和減緩 AD 病情發(fā)展的藥物。乙酰膽堿酯酶的抑制劑，通過

52、抑制中樞突觸間隙的乙酰膽堿酯酶的活性，阻止乙酰膽堿（Ach）的分解，提高患者腦中Ach的水平（Ach含量降低是AD主要病理變化之一），可以改善早期AD的癥狀，但并不是針對(duì)病因的根治。 第四種美金剛胺則是NMDA受體的拮抗劑，它不僅可拮抗興奮性氨基酸的興奮毒性，還可以防止細(xì)胞內(nèi)鈣的聚集及超載而造成神經(jīng)細(xì)胞的損傷和凋亡，應(yīng)用NMDA受體低親和性非競(jìng)爭(zhēng)拮抗劑治療癡呆，顯示了神經(jīng)保護(hù)和提高膽堿能功能的作用。這些藥物已被證實(shí)能夠改善記憶效

53、果，且副作用更少。遺憾的是，這些藥物并非對(duì)每個(gè)人都有效，而且其療效僅限于早期和中期 AD 患者。,崔德華 DH Chui,AD的新免疫療法,History of passive antibody therapy,In the early 1890s, Behring and Kitasato found that injecting nonlethal doses of tetanus toxin into animals cause

54、s the animals' blood to develop the ability to neutralize the toxin,in 1901, von Behring was awarded the first Nobel prize in Medicine.,崔德華 DH Chui,Inflammation and immune mechanisms in Alzheimer’s disease,Dennis J.

55、 Selkoe NATURE VOL 420 19/26 DECEMBER 2002,崔德華 DH Chui,The Aβ Life Cycle and Possible Points of Therapeutic Interventions,Tanzi RE Cell. 2005 25;120 545,崔德華 DH Chui,Adaptive Immunity,CNS as a immune privilege site: blood

56、-brain-barrierB cell and T cell epitope: implication for vaccine,崔德華 DH Chui,崔德華 DH Chui,崔德華 DH Chui,Improve Ab clearance while avoiding inflammatory effect,崔德華 DH Chui,Western blot,Confocal: intensity of CD11b IR,WT,E

57、P2-/-,Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Ab Phagocytosis Yet Lack Ab-activated Neurotoxicity,Am J Pathol, Vol. 166, No. 4, 2005,崔德華 DH Chui,Microglia lacking E prostanoid receptor subtype 2 h

58、ave enhanced Ab phagocytosis yet lack Ab-activated neurotoxicity,Microglia can be neuroprotective by phagocytosing Ab; however, this comes at the cost of activated innate immunity that causes paracrine damage to neurons.

59、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