基礎(chǔ)醫(yī)學(xué)神經(jīng)生物學(xué)PPT課件神經(jīng)系統(tǒng)退行性疾病基礎(chǔ)

1、Neurodegenerative Diseases崔德華崔德華 （DH Chui, MD, PhD,） 博士生導(dǎo)師博士生導(dǎo)師 Neuroscience, Research Institute and Dep. Of Neurobiology Peking University , China What Is Neurodegenerative diseases Hereditary and sporadic conditions which are Hereditary and sporadic conditions which are characterized by progressiv

2、e nervous system characterized by progressive nervous system dysfunction.dysfunction. These disorders are often associated with These disorders are often associated with atrophy (Apoptosis) of the affected central or atrophy (Apoptosis) of the affected central or peripheral nervous system structures

3、.peripheral nervous system structures. 崔德華崔德華 DH Chui 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, A

4、LS 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

5、Syndrome崔德華崔德華 DH Chui DH Chui大腦皮層變性大腦皮層變性：包括Alzheimer病、Pick病、CreutzfeldtJakob病(海綿狀變性)等。錐體外系統(tǒng)變性錐體外系統(tǒng)變性：包括Huntington病、HallervordenSpatz病、Wilson病(肝豆狀核變性)、Seitelberger病(神經(jīng)軸索型營養(yǎng)不良)、進行性肌陣攣型癲癇。病損在中腦與紋狀體者有Parkinson(帕金森)病、紋狀體黑質(zhì)變性、進行性核上型麻痹(PSP)等。腦干小腦變性腦干小腦變性：包括各種小腦型共濟失調(diào)、脊髓小腦變性、橄欖橋腦小腦變性(OPCA)、MachadoJoseph病等。

6、脊髓變性脊髓變性：包括進行性痙攣性截癱、進行性后索變性、后側(cè)索聯(lián)合變性、Friedreich共濟失調(diào)等。運動系統(tǒng)變性運動系統(tǒng)變性：包括各型運動神經(jīng)元病，如肌萎縮側(cè)索硬化(ALS)、進行性脊髓性肌萎縮(SMA)、進行性球麻痹等。自主神經(jīng)系統(tǒng)變性自主神經(jīng)系統(tǒng)變性：包括RileyDay癥候群(全自主神經(jīng)功能不全)、ShyDrager癥候群等。多系統(tǒng)變性多系統(tǒng)變性(MSA)：包括上述1、2、3、6等的混合類型。Neurodegenerative DiseasesClassification 崔德華崔德華 DH Chui DH ChuiParkinson disease崔德華崔德華 DH Chui DH

7、 Chui崔德華崔德華 DH Chui DH ChuiWhat Is Alzheimer Disease ?The Molecular Mechanisms of Alzheimer DiseaseTherapeutic Approach for Alzheimer Disease崔德華崔德華 DH Chui DH ChuiAlzheimer DiseaseThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband. Soon, a rapidly

8、 increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheimer (1907)奧古斯特奧古斯特 (51)(51)崔德華崔德華 DH Chui DH ChuiGrowth in

9、U.S. Population Aged 65+, 75+, and 85+65+75+85+1900192019401960198019902000202020402050020406080100Source: U.S. Census Bureau崔德華崔德華 DH Chui DH ChuiGenes Associated with Alzheimer DiseaseDiseaseGeneOnsetProductChromosomeEarlyAmyloid precursor protein (APP)21Presenilin 1 (PS1)14Presenilin 2 (PS2) 1Lat

10、eApolipoprotein E19LDL receptor-related protein (LRP)122-Macroglobulin (2M)12FE6511Chromosome 12 gene product12distinct from LRP and 2MChromosomal loci10崔德華崔德華 DH Chui DH ChuiClassification of Senile DementiaDSM-IV分類1.阿爾茨海默病阿爾茨海默病 (AD)(AD)2.血管性癡呆血管性癡呆 (CVD)(CVD)3.3.腦外傷所致癡呆腦外傷所致癡呆病所致癡呆病所致癡呆病所致癡呆病所致癡呆

11、病所致癡呆病所致癡呆病所致癡呆病所致癡呆病所致癡呆病所致癡呆9.9.物質(zhì)和軀體病所致癡呆物質(zhì)和軀體病所致癡呆10.10.其它癡呆其它癡呆(Lewy body dementia)(Lewy body dementia)崔德華崔德華 DH Chui DH ChuiThe AD diagnosisADAD臨床診斷的權(quán)威標準主要有臨床診斷的權(quán)威標準主要有3 3個：個：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)中的標準；美國國立神經(jīng)、語言疾病和卒中研究所(The National I

12、nstitute of Neurological and Communicative Disorders, NINCDS)與AD及相關(guān)疾病協(xié)會(The Alzheimers Disease and Related Disorders Association, ADRDA)制定的標準； 美國精神病診斷和統(tǒng)計手冊修訂第4版(the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Revised, DSM-IV)的標準。 #上述3個標準都是當(dāng)前國際公認的AD診斷標準，臨床上可根據(jù)需要選擇或互相參照使用。其中美國N

13、INCDS-ADRDA制定的標準中，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)用該標準及相關(guān)的診斷量表，AD臨床診斷的準確率可以提高到90%以上。崔德華崔德華 DH Chui DH ChuiAD clinical symptomAD clinical symptom神經(jīng)癥狀和體征神經(jīng)癥狀和體征認認知性癥知性癥狀狀記憶記憶非非認知性癥狀認知性癥狀精神和行為癥狀精神和行為癥狀失用失用失認失認失語失語執(zhí)行功能執(zhí)行功能崔德華崔德華 DH Chui DH Chui 崔德華崔德華 DH Chui DH ChuiAgentAgentRec

14、ognize Recognize sitesiteCompanyCompany samplesample Detect methodDetect methodINNOTEST hTau Aghuman tau, antigen in CSFInnogenetics, Belgium25 L CSFELISA microplate assayINNOTEST PHOSPHO-TAU(181P)tau(181p)Innogenetics, Belgium75 L CSFELISA microplate assayINNOTEST - AMYLOID(1-42) human -amyloid1-42

15、(A1-42)Innogenetics, Belgium25 L CSFELISA microplate assayINNO-LiPA ApoEapolipoprotein E genotypes e2, e3, and e4Innogenetics, Belgiumbloodline probe assayINNO-BIA AlzBio3A1-42,total-tau, P-tau181P Innogenetics, BelgiumUndiluted (75 L)/CSFbead-based multiparameter immunoassayCommercial Biomarker Kit

16、s for Diagnosis AD崔德華崔德華 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband. Soon, a rapidly increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid t

17、hem, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheimer (1907)崔德華崔德華 DH Chui DH Chui崔德華崔德華 DH Chui DH ChuiHowDiscrimination Between Earlier Period AD and Age-Associated Memory Impairment in Aging崔德華崔德華 DH Chui DH Chui 19861986年美國國立精神保健研究所提出年美國國立精神保健研究

18、所提出: :AAMIAAMI A Age-ge-A Associated ssociated M Memory emory I Impairmentmpairment 隨年齡增加出現(xiàn)非病理性的記憶力下降隨年齡增加出現(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)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)性智能衰退癡呆則是病理性的腦器質(zhì)性智能衰退。崔德華崔德華 DH Chui DH Chui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)別遺忘區(qū)別 健忘的老年人對做過事情的遺忘總是部分性的

19、； 癡呆的遺忘則是完全惡性的，記不起發(fā)生過的事情，似乎 此事已完全消失。 認知能力認知能力 健忘老人雖然記憶力下降，但對時間、地點、人物關(guān)系和周 圍環(huán)境的認知能力絲毫未減； 癡呆老人卻喪失了識別周圍環(huán)境的認知能力，分不清上下午， 不知季節(jié)變化，不知身在何處，有時甚至找不到回家的路。 生活能力生活能力 健忘老人雖會記錯日期有時前講后忘，但他們?nèi)阅芰侠碜约?的生活，甚至能照顧家人； 癡呆老人隨著病情加重，會逐漸喪失生活自理能力。 情緒變化情緒變化 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”，麻木不仁。思維變化思維變化 健忘老人對記憶力下降相當(dāng)苦惱，為了不致誤事，常記個備忘錄； 癡呆

20、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志之一。崔德華崔德華 DH Chui DH Chui90 y90 y崔德華崔德華 DH Chui 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崔德華崔德華 DH C

21、hui DH Chui Profound Loss of Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer DiseaseThe 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.

22、 The difference increased from 32% in the CDR =0.5 subgroup (n =4) to 69% in the CDR =3 subgroup (n =5).崔德華崔德華 DH Chui 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 st

23、ructures represent a semiquantitativeEC: entorhinal cortex SP : stratum pyramidale of the CA1 field ITC: :inferior temporal cortex SFC: superior frontal cortex崔德華崔德華 DH Chui DH ChuiWhat isWhat isP Paired aired HHelical elical F Filaments ilaments TauTau？ - PHF Tau -崔德華崔德華 DH Chui DH Chuia) The cytos

24、keleton b) components of the cytoskeleton崔德華崔德華 DH Chui DH ChuiSulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs崔德華崔德華 DH Chui DH Chui崔德華崔德華 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 51-year old womanwas susp

25、iciousness of her husband. Soon, a rapidly increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheimer (1907)崔德華崔德華

26、DH Chui DH Chui#APP : Amyloid precursor proteinAPP : Amyloid precursor protein崔德華崔德華 DH Chui DH ChuiWhat is Presenilin, APP and Ab ? b ? 崔德華崔德華 DH Chui DH ChuiMolecular features of presenilin and APP崔德華崔德華 DH Chui DH ChuiMolecular features of APP and Ab peptidesAPP : Amyloid precursor protein崔德華崔德華

27、DH Chui DH Chuipresenilin (Psn）Ab bAPP secretaseAAPresenilin complex崔德華崔德華 DH Chui DH ChuiAggregation of b b-amyloid is a multi step process崔德華崔德華 DH Chui DH ChuiCourtesy: Prof. C. Glabe, UC Irvine崔德華崔德華 DH Chui DH ChuiProposed actions of heat shock protein 70 and heat shock protein 40chaperones on

28、amyloid assemblyNATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15崔德華崔德華 DH Chui DH ChuiDirect and indirect effects of molecular chaperones on disease protein toxicityNATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15崔德華崔德華 DH Chui DH ChuiProtein misfolding diseases associated with m

29、olecular chaperonesNATURE REVIEWS | NEUROSCIENCE VOLUME 6 | JANUARY 2005 | 15崔德華崔德華 DH Chui DH Chui PresenilinAb b cascades in AD 崔德華崔德華 DH Chui DH ChuiTransgenic mice with presenilin 1 mutations hPS1/ FVB/ N miceMicroinjection methodFVB/N mice2) pAxCAwt-vector3) h-PDGF promoter4) hPS1-L286V-cDNA hP

30、S1-H163R-cDNAChui, DH. et al. Nat Med 5, 560-4. (1999)崔德華崔德華 DH Chui DH ChuiDark neuron counts are significantly higherr in aged PS1 mutant mice without amyloid plaque formationChui, DH. et al. Nat Med 5 5, 560-4. (1999)崔德華崔德華 DH Chui DH ChuiNeurons with intracellular Ab b-positive deposits Chui, D.

31、H. et al. Nat Med 5, 560-4. (1999)崔德華崔德華 DH Chui DH Chui iAbbnegative / / TUNEL+iAbbpositive / / TUNEL+Mean, SEM* * T h e firs t n o tic e a b le s y m p to m s o f th e illn e s s o f th is 5 1 -y e a r o ld w o m a nw a s s u s p ic io u s n e s s o f h e r h u s b a n d . S o o n , a ra p id ly i

32、n c re a s in g m e m o ryim p a irm e n t b e c a m e e v id e n t. S h e c o u ld n o lo n g e r o rie n t h e rs e lf in h e ro w n d w e llin g , d ra g g e d o b je c ts h e re a n d th e re a n d h id th e m , a n d , a t tim e sb e lie v in g th a t p e o p le w e re o u t to m u rd e r h e r

33、, s ta rte d to s c re a m lo u d ly .A lo is A lz h e im e r (1 9 0 7 )Chui et al, J Alzheimers Dis. 2001 Apr;3(2):231-239 Chui, DH. et al. J of Alzheimer Disease. 2001; 3: 231 崔德華崔德華 DH Chui DH Chui Impairment of LTP in brain of 3 x TG The first noticeable symptoms of the illness of this 51-year o

34、ld womanwas suspiciousness of her husband. Soon, a rapidly increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheim

35、er (1907)崔德華崔德華 DH Chui DH ChuiA Ab bAmyloid aggregationsSenile plaquesPHF-TauPHF-TauNeuronal deathAPPA Ab bAlzheimer disease DementiaDementiaHypothesis of Amyloid CascadeExtracelluar AbPathogenic role of the PS-1 mutation is Up stream of amyloid cascadeEnhanced production of Ab42Intracellular Ab42

36、Neuronal degenerationAlzheimer disease DementiaDementia崔德華崔德華 DH Chui DH ChuiSummary (1)(1)Mutations of presenilin 1 (PS-1) enhance the generation of Ab1Ab1-42, indicating that PS-1 is involved in amyloidogenesis.We firstly found that neurodegeneration was significantly accelerated in older aged mic

37、e with mutant PS-1, without amyloid plaque formation.There were significantly more neurons containing intracellularly deposited AbAb in aged mutant transgenic mice. Pathogenic role of the PS-1 mutation is Up stream of amyloid cascade。崔德華崔德華 DH Chui DH ChuiFormation of TAU inclusions in knock-in mice

38、 with familial Alzheimers disease (FAD) mutation of presenilin 1(PS1)TanemuraTanemura，Chui et al. JBC,2005Chui et al. JBC,2005崔德華崔德華 DH Chui DH ChuiImmunostaining with PS1 and PHF-tauChui et al. J Neurosci Res. 1998, 1;53(1):99 Chui et al. J Neurosci Res. 1998, 1;53(1):99 The first noticeable sym pt

39、om s of the illness of this 51-year old w om anw as suspiciousness of her husband. S oon, a rapidly increasing m em oryim pairm ent becam e evident. S he could no longer orient herself in herow n dw elling, dragged objects here and there and hid them , and, at tim esbelieving that people w ere out t

40、o m urder her, started to scream loudly.A lois A lzheim er (1907)PS1-NAT-8PS1-C AT-8崔德華崔德華 DH Chui DH Chuitau(ins.)tau(sol.)PS199PS262PS396PS404PS422AT8Tau-1wPS1mPS1 (hetero)mPS1 (homo)wPS1mPS1 (hetero)mPS1 (homo)Western blots of SDS-insoluble and RIPA-soluble materialsTanemuraTanemura，Chui et al. J

41、BC,2005Chui et al. JBC,2005崔德華崔德華 DH Chui DH ChuiTanemuraTanemura，Chui et al. JBC,2005Chui et al. JBC,2005The formation and accumulation of filamentous tau were Accelerated Accelerated by activating GSk-3by activating GSk-3b b n n The f i r st not i ceabl e sympt oms of t he i l l ness of t hi s 51-

42、 year ol d womanwas suspi ci ousness of her husband. Soon, a r api dl y i ncr easi ng memor yi mpai r ment became evi dent . She coul d no l onger or i ent her sel f i n herown dwel l i ng, dr agged obj ect s her e and t her e and hi d t hem, and, at t i mesbel i evi ng t hat peopl e wer e out t o m

43、ur der her , st ar t ed t o scr eam l oudl y. Al oi s Al zhei mer ( 1907)GSK-3b bGSK-3b b(Ser-9)Western blot of GSK-3b bwPS1mPS1 (hetero)mPS1 (homo)1600014000120001000080006000wildheterohomoRelative activity (cpm/mg protein/min)GSk-3b b Activity崔德華崔德華 DH Chui DH ChuiSummary ( (2 2) )PS1 mutations co

44、ntribute to the onset PS1 mutations contribute to the onset of AD not only by enhancing A1-42 of AD not only by enhancing A1-42 production but by also accelerating production but by also accelerating the formation and accumulation of the formation and accumulation of filamentous tau.filamentous tau.

45、TanemuraTanemura，Chui et al. JBC,2005Chui et al. JBC,2005崔德華崔德華 DH Chui DH ChuiPS1 may act as a molecular tether, connecting GSK-3 with important substrates. PS1GSK-3PS1TauTauPS1-cateninPS1 AbPhosphorylationof tauNFT Cell death Inhibition ofprotein synthesisGSK-3GSK-3GSK-3-cateninA42 productionP53？崔

46、德華崔德華 DH Chui DH ChuiJ. Biol. Chem., Vol. 278, Issue 49, 48872-48879Domains of p53 that regulate its association with GSK3b b崔德華崔德華 DH Chui DH ChuiNeuronal Degeneration Activates p53 Promoter ？Intracellular Ab b42崔德華崔德華 DH Chui DH Chui RT-PCR Analyses of p53 mRNA in APP-Tg (3M, 6M and 10M)Oyagi, Asa

47、hara, Chui et al. FASEB J. 2005Oyagi, Asahara, Chui et al. FASEB J. 2005崔德華崔德華 DH Chui DH Chui Immunoblotting analysis, immunocytochemical staining and double immunostaining in AD brainThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband. Soon, a ra

48、pidly increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheimer (1907)Oyagi, Asahara, Chui et al. FASEB J. 2005Oya

49、gi, Asahara, Chui et al. FASEB J. 2005崔德華崔德華 DH Chui DH ChuiSummary (3)Intracellular Ab b42 directly activated the p53 promoter resulting in p53-dependent apoptosis.Remarkably, accumulation of both Ab b42 and p53 was found in some degenerating-shape neurons in both mice and AD cases. Thus, the intra

50、cellular Ab b42/p53 pathway may be directly relevant to neuronal loss in AD. Oyagi, Asahara, Chui et al. FASEB J. 2005Oyagi, Asahara, Chui et al. FASEB J. 2005崔德華崔德華 DH Chui DH ChuiQuickTime遣蓃蒮蒊 闘恚蓈社蒓赦贍菣潛敲蓅蒒蒨繕薔濠僑菫墻菂欽颣髒黔菑臖Structure of Human GSK3 崔德華崔德華 DH Chui DH ChuiGSK-3a a is required for Ab b pro

51、ductionCHO-APP695 cells were transfected with GFP or GSK-3a, and secreted Ab42 崔德華崔德華 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 51-year old womanwas suspiciousness of her husband. Soon, a rapidly increasing memoryimpairment became evident. She could no longer orient herself

52、 in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois Alzheimer (1907)Lithium blocks ALithium blocks Ab b accumulation in cultured neurons and in the accumulation in cultured neurons and in the brai

53、ns of mice overproducing Abrains of mice overproducing Ab b peptides 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. 崔德華崔德華 DH Chui DH ChuiThe first noticeable symptoms of the illness of this 5

54、1-year old womanwas suspiciousness of her husband. Soon, a rapidly increasing memoryimpairment became evident. She could no longer orient herself in herown dwelling, dragged objects here and there and hid them, and, at timesbelieving that people were out to murder her, started to scream loudly.Alois

55、 Alzheimer (1907)崔德華崔德華 DH Chui DH ChuiEffects of GSK-3Effects of GSK-3b b on AD on ADGSK-3b boAb bNFT formationNeuronal lossSynapse lossMemory lossAktkinesinTau accumulationtauThis suggests that inhibiting GSK-3b b is a promising AD therapyp53Axonal transportdegradation崔德華崔德華 DH Chui DH ChuiTherape

56、utic Approach for Alzheimer Disease崔德華崔德華 DH Chui DH ChuiTherapeutic Approach for Alzheimer Disease1. ADAD的一般護理、經(jīng)濟、法律的一般護理、經(jīng)濟、法律2. 2. 西醫(yī)藥治療西醫(yī)藥治療 膽堿酯酶抑制劑療法膽堿酯酶抑制劑療法 ADAD的新免疫療法的新免疫療法 抗炎療法抗炎療法 gamagama和和beta-APPbeta-APP分泌酶抑制劑療法分泌酶抑制劑療法 GSK-3betaGSK-3beta抑制劑療法抑制劑療法 其他其他3. 3.中醫(yī)藥治療中醫(yī)藥治療崔德華崔德華 DH Chui DH C

57、hui乙酰膽堿與乙酰膽堿與1 1）中樞乙酰膽堿含量下降、膽堿乙?；福ǎ┲袠幸阴Ｄ憠A含量下降、膽堿乙?；福–hATChAT）、膽堿酯酶）、膽堿酯酶 （AchEAchE）活性降低或乙酰膽堿受體（活性降低或乙酰膽堿受體（M-AchRM-AchR、N-AchRN-AchR）敏感性降低是）敏感性降低是 ADAD的主要的主要病理改變之一。病理改變之一。2 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)）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)2-42-4層層崔德華崔德華 DH Chui DH ChuiAcetylcholine a) Ach synthesis b) Ach

58、degradation Tau崔德華崔德華 DH Chui DH ChuiMemory loss-DementiaMemory loss-Dementia崔德華崔德華 DH Chui DH Chui膽堿抑制劑與膽堿抑制劑與膽堿抑制劑膽堿抑制劑；安理申（安理申（DonapezilDonapezil，多奈哌齊，商品名，多奈哌齊，商品名AriceptAricept) )艾斯能艾斯能( (rivastigminerivastigmine，利凡斯的明，商品名，利凡斯的明，商品名ExelonExelon) )加蘭他敏（加蘭他敏（galantaminegalantamine，加蘭他敏，商品名，加蘭他敏，商品

59、名ReminylReminyl）美金剛胺美金剛胺 （MemantineMemantine）利用藥物減輕早期利用藥物減輕早期 AD AD 患者的癥狀是可能的。到患者的癥狀是可能的。到 2002 2002 年年 1 1 月，月，F(xiàn)DA FDA 已批準了用于提高記憶力和減緩已批準了用于提高記憶力和減緩 AD AD 病情病情發(fā)展的藥物。發(fā)展的藥物。乙酰膽堿酯酶的抑制劑，通過抑制中樞突觸間隙的乙酰膽堿酯酶的活性，阻止乙酰膽堿（乙酰膽堿酯酶的抑制劑，通過抑制中樞突觸間隙的乙酰膽堿酯酶的活性，阻止乙酰膽堿（AchAch）的分解，提高患）的分解，提高患者腦中者腦中AchAch的水平（的水平（AchAch含量降

60、低是含量降低是ADAD主要病理變化之一），可以改善早期主要病理變化之一），可以改善早期ADAD的癥狀，但并不是針對病因的根治。的癥狀，但并不是針對病因的根治。 第四種美金剛胺則是第四種美金剛胺則是NMDANMDA受體的拮抗劑，它不僅可拮抗興奮性氨基酸的興奮毒性，還可以防止細胞內(nèi)鈣的聚集受體的拮抗劑，它不僅可拮抗興奮性氨基酸的興奮毒性，還可以防止細胞內(nèi)鈣的聚集及超載而造成神經(jīng)細胞的損傷和凋亡，應(yīng)用及超載而造成神經(jīng)細胞的損傷和凋亡，應(yīng)用NMDANMDA受體低親和性非競爭拮抗劑治療癡呆，顯示了神經(jīng)保護和提高受體低親和性非競爭拮抗劑治療癡呆，顯示了神經(jīng)保護和提高膽堿能功能的作用。膽堿能功能的作用。這些