北大神經(jīng)生物學(xué)課件6-3神經(jīng)系統(tǒng)退行性疾病基礎(chǔ)

Immunoblottinganalysis immunocytochemicalstaininganddoubleimmunostaininginADbrain Oyagi Asahara Chuietal FASEBJ 2005 崔德華DHChui Summary 3 IntracellularA 42directlyactivatedthep53promoterresultinginp53 dependentapoptosis Remarkably accumulationofbothA 42andp53wasfoundinsomedegenerating shapeneuronsinbothmiceandADcases Thus theintracellularA 42 p53pathwaymaybedirectlyrelevanttoneuronallossinAD IntracellularA 42maycausep53 dependentneuronalapoptosisthroughactivationofthep53promoter thusdemonstratinganalternativepathogenesisinAD Oyagi Asahara Chuietal FASEBJ 2005 崔德華DHChui StructureofHumanGSK3 崔德華DHChui GSK 3aisrequiredforAbproduction CHO APP695cellsweretransfectedwithGFPorGSK 3a andsecretedAb42 崔德華DHChui LithiumblocksAbaccumulationinculturedneuronsandinthebrainsofmiceoverproducingAbpeptides EmbryoniccorticalneuronswereinfectedwithSFVcontainingwild typeAPP APP WT orAPP Swedish KM670 671NL thentreatedwithLiClfor24h 崔德華DHChui 崔德華DHChui EffectsofGSK 3bonAD GSK 3b oAb NFTformation Neuronalloss Synapseloss Memoryloss Akt kinesin Tauaccumulation GSK 3 Inhibitor tau ThissuggeststhatinhibitingGSK 3 isapromisingADtherapy p53 Axonaltransportdegradation 崔德華DHChui TherapeuticApproachforAlzheimerDisease 崔德華DHChui TherapeuticApproachforAlzheimerDisease 1 AD的一般護理 經(jīng)濟 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DHChui 乙酰膽堿與AD 1 中樞乙酰膽堿含量下降 膽堿乙?；?ChAT 膽堿酯酶 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DHChui Acetylcholinea Achsynthesisb Achdegradation Tau 崔德華DHChui Memoryloss Dementia Alzheimerdisease 崔德華DHChui 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 FDA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NMDA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 這些藥物已被證實能夠改善記憶效果 且副作用更少 遺憾的是 這些藥物并非對每個人都有效 而且其療效僅限于早期和中期AD患者 崔德華DHChui AD的新免疫療法 Historyofpassiveantibodytherapy Intheearly1890s BehringandKitasatofoundthatinjectingnonlethaldosesoftetanustoxinintoanimalscausestheanimals bloodtodeveloptheabilitytoneutralizethetoxin in1901 vonBehringwasawardedthefirstNobelprizeinMedicine 崔德華DHChui InflammationandimmunemechanismsinAlzheimer sdisease DennisJ SelkoeNATUREVOL42019 26DECEMBER2002 崔德華DHChui TheA LifeCycleandPossiblePointsofTherapeuticInterventions TanziRECell 200525 120545 崔德華DHChui AdaptiveImmunity CNSasaimmuneprivilegesite blood brain barrierBcellandTcellepitope implicationforvaccine 崔德華DHChui 崔德華DHChui 崔德華DHChui ImproveAbclearancewhileavoidinginflammatoryeffect 崔德華DHChui Westernblot Confocal intensityofCD11bIR WT EP2 MicrogliaLackingEProstanoidReceptorSubtype2HaveEnhancedAbPhagocytosisYetLackAb activatedNeurotoxicity AmJPathol Vol 166 No 4 2005 崔德華DHChui MicroglialackingEprostanoidreceptorsubtype2haveenhancedAbphagocytosisyetlackAb activatedneurotoxicity MicrogliacanbeneuroprotectivebyphagocytosingAb however thiscomesatthecostofactivatedinnateimmunitythatcausesparacrinedamagetoneurons AblationofEprostanoidreceptorsubtype2significantlyincreasedmicroglial mediatedclearanceofAbpeptidesfro