北大神经生物学课件6-2神经系统退行性疾病基础

WhatisPresenilin,APPandAβ?崔德华DHChuiMolecularfeaturesofpresenilinandAPP崔德华DHChuiMolecularfeaturesofAPPandAβpeptidesAPP:Amyloidprecursorprotein崔德华DHChuipresenilin(Psn）Aβ42APPγ−secretaseAßAßPresenilincomplex崔德华DHChuiAggregationofβ-amyloidisamultistepprocess崔德华DHChuiCourtesy:Prof.C.Glabe,UCIrvine崔德华DHChuiProposedactionsofheatshockprotein70andheatshockprotein40chaperonesonamyloidassemblyNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德华DHChuiDirectandindirecteffectsofmolecularchaperonesondiseaseproteintoxicityNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德华DHChuiProteinmisfoldingdiseasesassociatedwithmolecularchaperonesNATUREREVIEWS|NEUROSCIENCEVOLUME6|JANUARY2005|15崔德华DHChuiPresenilinAβcascadesinAD崔德华DHChuiTransgenicmicewithpresenilin1mutationshPS1/FVB/NmiceMicroinjectionmethod1)FVB/Nmice2)pAxCAwt-vector3)h-PDGFpromoter4)hPS1-L286V-cDNAhPS1-H163R-cDNAChui,DH.etal.NatMed5,560-4.(1999)崔德华DHChuiDarkneuroncountsaresignificantlyhigherrinagedPS1mutantmicewithoutamyloidplaqueformationChui,DH.etal.NatMed5,560-4.(1999)崔德华DHChuiNeuronswithintracellularAβ-positivedepositsChui,D.H.etal.NatMed5,560-4.(1999)崔德华DHChuiAnalysisAnalysisofapoptosisbydoublestainingwithAofapoptosisbydoublestainingwithAβ42β42(green)and(green)andTUNEL(red)TUNEL(red)PS1FADPS1FADiAβ42−negative/TUNEL+iAβ42−positive/TUNEL+controlAD%%Mean,SEM0.050.10*@#0.00Chuietal,JAlzheimersDis.2001Apr;3(2):231-239Chui,DH.etal.JofAlzheimerDisease.2001;3:231崔德华DHChuiImpairmentofLTPinbrainof3xTG崔德华DHChuiAβAβAmyloidaggregationsAmyloidaggregationsSenileplaquesSenileplaquesPHF-TauPHF-TauNeuronaldeathNeuronaldeathAPPAPPAβAβAlzheimerdiseaseDementiaHypothesisofAmyloidCascadeExtracelluarAbPSPS--1mutation1mutationPathogenicroleofthePS-1mutationisUpstreamofamyloidcascadeEnhancedproductionofAb42IntracellularAb42NeuronaldegenerationAlzheimerdiseaseDementia崔德华DHChuiSummary(1)1.Mutationsofpresenilin1(PS-1)enhancethegenerationofΑβ1-42,indicatingthatPS-1isinvolvedinamyloidogenesis.2.WefirstlyfoundthatneurodegenerationwassignificantlyacceleratedinolderagedmicewithmutantPS-1,withoutamyloidplaqueformation.3.ThereweresignificantlymoreneuronscontainingintracellularlydepositedΑβ42inagedmutanttransgenicmice.PathogenicroleofthePS-1mutationisUpstreamofamyloidcascade。崔德华DHChuiFormationofTAUinclusionsinknock-inmicewithfamilialAlzheimer'sdisease(FAD)mutationofpresenilin1(PS1)Tanemura，Chuietal.JBC,2005崔德华DHChuiImmunostainingwithPS1andPHF-tauChuietal.JNeurosciRes.1998,1;53(1):99PS1-NAT-8PS1-CAT-8崔德华DHChuitau(ins.)tau(sol.)PS199PS262PS396PS404PS422AT8Tau-1wPS1mPS1(hetero)mPS1(homo)wPS1mPS1(hetero)mPS1(homo)WesternblotsofSDS-insolubleandRIPA-solublematerialsTanemura，Chuietal.JBC,2005崔德华DHChuiTanemura，Chuietal.JBC,2005TheformationandaccumulationoffilamentoustauwereAcceleratedbyactivatingGSk-3βnGSK-3βGSK-3β(Ser-9)WesternblotofGSK-3βwPS1mPS1(hetero)mPS1(homo)1600014000120001000080006000wildheterohomoRelativeactivity(cpm/mgprotein/min)GSk-3βActivity崔德华DHChuiSummary(2)PS1mutationscontributetotheonsetofADnotonlybyenhancingAβ1-42productionbutbyalsoacceleratingtheformationandaccumulationoffilamentoustau.Tanemura，Chuietal.JBC,2005崔德华DHChuiPS1mayactasamoleculartether,connectingGSK-3ßwithimportantsubstrates.PS1GSK-3ßPS1TauTauPS1ß-cateninPS1AβPhosphorylationoftauNFTCelldeathInhibitionofproteinsynthesisGSK-3ßGSK-3ßGSK-3ßß-cateninAß42productionP53？崔德华DHChuiJ.Biol.Chem.,Vol.278,Issue49,48872-48879Domainsofp53thatregulateitsassociationwithGSK3β崔德华DHChuiNeuronalDegenerationActivatesp53Promoter？IntracellularAβ42崔德华DHChuiRT-PCRAnalysesofp53mRNAinAPP-Tg(3M,6Mand10M)Oyagi,Asahara,Chuietal.FASEBJ.2005崔德华DHChui 幻灯片编号1 幻灯片编号2 幻灯片编号3 幻灯片编号4 幻灯片编号5 幻灯片编号6 幻灯片编号7 幻灯片编号8 幻灯片编号9 幻灯片编号10 幻灯片编号11 幻灯片编号12 幻灯片编号13 幻灯片编号14 幻灯片编号15 幻灯片编号16 幻灯片编号17 幻灯片编号18 幻灯片编号19 幻灯片编号20 幻灯片编号21 幻灯片编号22 PS1mayactasamoleculartether,connecting�GSK-3ßwithimportantsubstrates. 幻灯片编号24 幻灯片编号25 幻灯片编号26