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    首頁 3. Failure醫學電子書

    3. Failure醫學電子書.pdf

    3. Failure醫學電子書

    小嘎
    2018-04-02 0人閱讀 舉報 0 0 暫無簡介

    簡介:本文檔為《3. Failure醫學電子書pdf》,可適用于醫藥衛生領域

    PoreFormingNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureLuisGAguayo,JorgeParodi,FernandoJSepuacutelveda,andCarlosOpazoAbstractCorticalandhippocampalsynapsedensitiesarereducedinAlzheimerrsquosdisease(AD),andthisstronglycorrelateswithmemorydysfunctionItisnowbelievedthatthesechangesinneuronalnetworkingoccurattheonsetofADandmayleadtotheneuronallossdisplayedinlaterstagesofthedisease,whichischaracterizedbyseverecognitiveandbehavioralimpairmentsMountingevidenceindicatesthatamyloidb(Ab)oligomersareresponsibleforsynapticdisconnectionsandneuronaldeathOneofthemainconsequencesofAboligomersinteractionwithneuronsisanincreaseinintracellularCaconcentrationthatcould,whenlargeenough,causeamarkedalterationinionichomeostasisIthasalsobeenpostulatedthatCainfluxoccurswhenAboligomersinducetheopeningofCachannelsorthedisruptionoftheplasmamembraneWerecentlyfoundthattheeffectsofAboligomersonsynaptictransmissionaresimilartoporeformingtoxins,suchasalatrotoxin,aneurotoxinfromtheblackwidowspiderHere,wediscussevidencesupportinganeurotoxinlikemechanismfortheeffectsinducedbyAboligomersonneuronalmembranes,whichcouldexplainthealterationsinthefunctionalityofsynapsesinthecentralnervoussysteminADthatleadstomajorneurodegenerationwithtimeofexposuretoAboligomersAbbreviationsAb:amyloidbpeptide,AD:AlzheimerrsquosdiseaseaLTX:alatrotoxinAbPP:amyloidbproteinprecursorCa:calciumLTP:longtermpotentiationpS:picoSiemenIncreaseinSolubleAbOligomersisaKeyFactorforAlzheimerrsquosDiseaseOnsetOneofthemainhistopathologicalfeaturesofAlzheimerrsquosdisease(AD)isthepresenceofextracellularproteinaceousdepositsinthebrain,identifiedassenileplaques,whichareenrichedinamyloidb(Ab)peptideoligomersItiswidelyRBMaccioniandGPerry(eds)CurrentHypothesesandResearchMilestonesinAlzheimerrsquosDiseaseDOI:,copySpringerScienceBusinessMedia,LLCLGAguayo(),JParodi,FJSepuacutelveda,andCOpazoDepartmentofPhysiology,UniversityofConcepcioacuten,ConcepcioacutenChileemail:laguayoudecclLGAguayoetalacceptedthatADonsetcanbeinitiallytriggeredbyinteractionofAboligomerswiththebrainparenchyma,However,thespecificbiochemicalstructuralcharacteristicsoftheAboligomersthatinducetheneurotoxicityobservedinADhavenotbeenthoroughlyidentified,butithasbeensuggestedthatsolubleAboligomers(rangingfromtokDa),arekeydeterminantsforneurotoxicity,includingsynapticfailure,observedinADInagreementwiththis,thelevelsofsolubleAboligomersappeartocorrelatewellwiththeseverityofADdysfunction,Interestingly,thesesolubleoligomersproducedsynaptictoxicityasexpressedbyinhibitionofhippocampallongtermpotentiation(LTP)invivoandalterationsincomplexanimallearningbehaviors,ThesedatastronglysuggestthatADonset,probablyassociatedtoamildsynapticdysfunction,occursbeforeamyloidplaqueformationHowever,themechanism(preorpostsynaptic)bywhichAboligomerscausesynapticdysfunctionislargelyunknownAdditionally,previousstudieshaveshownthatAboligomersaffectneuronalmorphologyandsurvival,andproduceaxonalanddendriticdystrophyThesealterationsseemtooccurfollowingamyloiddepositioninthebrain,indicatingthataccumulationofAboligomersprecedesthealterationsinneuriticmorphologyThus,thesestudiesprovideevidencesuggestingadecreaseinneuronalnetworkinginADasaproductofAboligomersaccumulationHowthisAboligomersaccumulationproducessuchastrongdisruptioninsynaptictransmissioninthecentralnervoussystemiscurrentlyunderactiveinvestigationwiththeaimofdiscoveringtherapeutictargetsanddiseasemodifyingtreatmentsEarlySynapticAlterationsPrecedeADOnsetIthasbeenpostulatedthatalterationsinsynapticplasticitymightbetheprimaryfailureresponsibleforthecognitivedysfunctioninADHowever,thescopeandstrengthofstudiessupportingthischallengingsuggestionisonlynowbeingconsideredatthecellularandmolecularlevelItiscurrentlyknownthatsynaptictransmissioninthebraincanbealteredbyspecificandnonspecificmechanismsatpreorpostsynapticsitesInthecaseofAb,studiesinhippocampalneuronstreatedwithsyntheticAboligomersshowedthatitreducedthenumberofsynapticcontactsandvariouspreandpostsynapticproteins,thussuggestingextensivealterationsinneuronalconnectivity,Inagreement,transgenicmicemodelsoverexpressingamyloidbproteinprecursor(AbPP)showedamarkedreductioninsynaptophysinlevelsInterestingly,itwasreportedthatsynapselosswashighlycorrelatedtoneurologicaldeficitsobservedinmildtoseverestagesofAD,supportingadirectlinkbetweencognitivefunctionsandneurotransmissionFurthermore,itwasshownthatearlychangesinsynapticmorphologyandmarkerssuchassynaptophysincorrelatebettertodiseaseprogression,suggestingthatsynapticcomponentsarethemostprobabletargetsfortheearlyneurotoxicactionsofAboligomersSpecifically,severalproteinshavingwelldefinedfunctionsinsynapticvesicleendocytosis,PoreFormingNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureincludingAP,AP,dynamin,andsynaptotagmin,havebeenreportedtobeextensivelyalteredinADHowAboligomersareabletoproducethismyriadofeffectsonsynapticproteinsisunknown,butitispossiblethatthesechangeshaveacommontriggeringmembranemechanismNevertheless,thesefindingssuggestthatADisassociatedwithfailureinthecellularmachineryresponsibleforsynapticreleaseandrecyclingAdditionally,alterationsinsynapticproteinsproducedbytheactionofAboligomerscanexplainitsfunctionalimpactinmodelsofcellularlearningandmemory,suchasLTPHere,weareproposingthatAboligomersaffectsynaptictransmissionthroughitschannelformingproperties(seebelow)IfAboligomerscausesynaptictransmissionfailurebyporeformation,thefollowingstepsmustoccurforthismechanismtobedemonstrated:()interactionofAboligomerswithneuronalmembranes,()poreformation,()increaseinintracellularcalcium,()sustainedincreaseinvesicularrelease,and()vesiculardepletion(synapticfailure)WehavefoundthatAboligomersproduceseveralofthesecellularevents,asdescribedbelowCalciumandSynapticDysfunctioninADThereisacurrentgrowingbodyofevidencesuggestingtheexistenceofadysfunctioninintracellularCahomeostasisinADPrefibrillarAboligomershavebeenshowntoelevateCainneuronsThisincreaseinintracellularCacanfollowreceptoractivation,modulationofvoltageactivatedCachannels,andinfluxvianonselectivecationsorbyporechannelsformedbyAboligomersAnalysisofthepeptidesecondarystructuresuggeststhepossibilityofionchannelformationinducedbymembraneboundAboligomersTheAbporechannelhypothesiswasfirstproposedbyRojasandcollaboratorsattheNIHusingartificialmembranesTheydemonstratedtheformationofporeswithAbndashthatwerehighlycationselective,allowingpermeationofCa,Na,andCsTheseearlystudiesinsyntheticmembraneswerevalidatedinmembranesfromhypothalamiccelllinesInterestingly,cholesterollevelsfavoredtheformationofAbchannelsinartificialandhypothalamicmembranes,SinglechannelmeasurementsshowedthatthebehavioroftheAbndashinducedchannelswereexceptionallycomplex,inadditiontotheirstrongdependencyonCsconcentrationandvariabilityofsinglechannelconductance(ndashpS)Also,itwasfoundthatZn,knowntobindAbinsolution,blockedioncurrentflow,suggestingthattheAbamyloidporecanbeapharmacologicaltargetAlltogether,thedatasuggestthatAboligomersdonotformaunique,wellbehavedtypeofionchannel,buttheycontributetotheformationofacomplexmultiplefamilyofconductingporesInterestingly,usinganldquooligomerenrichedrdquoformofAb,anincreasewasshowninlipidbilayerconductance,intheabsenceofunitaryevents,addingtothecomplexbehaviorofthepeptideinthemembraneInconclusion,itisevidentthatAboligomersareabletoincreasetheconductanceinartificialmembranes,butthishasnotbeendemonstratedinbiologicallyrelevantcell(neuron)membranesLGAguayoetalProposedNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureThecellularandmolecularmechanismsthatinduceADarelargelyunknownanddeterdevelopmentofeffectivediseasepreventingmodifyingtherapiesThemostacceptedworkinghypothesisofADisthatexcessofAboligomerseither()bindtomembranereceptorsaffectingtheirfunctions,()interferewithsignalingcascades,or()directlydisruptneuronalmembranescausingporeformationthusleadingtoalterationsinionichomeostasisAlthoughthelatterisanattractivehypothesisbecauseitcouldexplainseveraleffectsofAboligomersonbrainsynapses,ithasnotbeendocumentedtooccurinbrainneuronalmembranesandthiscouldbeduetothehighcomplexityofbiologicalmembranes,suchasheterogeneityinnativeionchannelsandreceptorsInanattempttoelucidatethemechanismbywhichAboligomersinducesynaptotoxicity,weundertookanexperimentalapproachtocharacterizehowAboligomeraffectsynaptictransmissionandcomparedtheseeffectswiththoseproducedbyneurotoxinsknowntoformmembraneporesWefoundthattheeffectsofAboligomers,althoughathigherconcentrations(nMvspM),wereverysimilartothoseofporeformingalatrotoxin(aLTX,kDa)allowingustosuggestthatitsneurotoxicitywasdependentonporeformationwithinthecellmembraneForexample,similartoaLTX,,wefoundthatAboligomersdirectlyincreasedmembraneconductanceandintracellularcalciumcausinganearlyincreaseandadelayedfailureinsynapticrelease(Figb)FigEffectsofAbndasholigomersonsynapticactivityofhippocampalneuronsaTheschemeillustratespreandpostsynapticcomponentsofacentralsynapseThevesiclesarereleasedinacalciumdependentfashionPresynapticactivitycanbedeterminedbythepresenceofvesicularproteins(SV)orbythestainingofsynapticvesicleswithfluorescentprobessuchasFMndash(reddots)ThepostsynapticmembranecurrentsassociatedtothevesicularreleaseandpostsynapticreceptordensitycanbeanalyzedusingthepatchclamptechniquebTimedependentbiphasiceffectofnMAboligomersonsynaptictransmissioninhippocampalneuronsTheeffectsofAboligomerswereblockedbyloweringextracellularcalciumorbyaddingNa(brokenline)Thevalueswereobtainedfromthreeindependentexperiments(SeeColorPlates)PoreFormingNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureIthasbeenrecognizedforseveralyearsthataLTXcanaltermembranepermeabilitygeneratingnonselectiveionicporesTherefore,themechanismfortoxicitydependsonattachmenttothecellmembraneanddisruptionofionicpermeabilityThemajorityofstudieswithaLTXstronglysupporttheideathatthemainincreaseinintracellularcalciumresultsfromCaentrythroughnonselectivecationchannelsformedbymembraneboundtoxinsOnceboundtoneuromuscularjunctionmembranes,aLTXformsoligomericstructuresthatstimulateexhaustivereleaseofneurotransmittersOneofthemostdistinguishingfeaturesofaLTXonthesynapseisthatitproducesamarkedvesiculardepletionInterestingly,wefoundthatAboligomerswereabletomimicalloftheseeffectsinhippocampalneuronsForexample,whenexaminingtheeffectsofnanomolarconcentrationsofAbndasholigomersonthespontaneoussynapticactivityinlivinghippocampalneurons,usingpatchclampandfluorometricimaging(FluoandFMndash)(Figa),wefoundthattheeffectsoflowconcentrationsofAboligomersonsynaptictransmissionwerebiphasic,witharapidfacilitationfollowedbyadelayedfailure(Figb)Wealsofoundthatthedelayedsynapticfailurecorrelatednicelywithadecreaseinseveralpresynapticproteins,suchasSV(Figaandb)TheseresultsindicatethatAboligomerswereabletoproduceasignificantlossofconnectivityincentralneuronsparticipatinginlearningandmemory,whichisinagreementwiththeideathatcognitivealterationsinADareassociatedtoasynapticfailure,Moreimportantly,blockadeoftheAbporewithasmallpeptide,previouslyshowntoinhibitAboligomersinducedincreaseonmembranepermeability,protectedthehippocampalneuronsfromsynaptotoxicity,maintaininghighlevelsofSVassociatedtoneurotransmittervesiclesinthepresenceofAboligomers(Figsband)WeproposethatfuturestudiesofthismembranephenomenonwillrevealthatthetargetofAboligomersarenotanotherprotein,butwillshowthatAboligomersthemselvesarethecellulartargettherebyexplainingthefailureofpharmacologicalFigTheeffectofAbndasholigomersonvesicularSVlevelwasblockedbyNaaWesternblotsforSVobtainedfromhippocampalneuronsincubatedintheabsence(control)orpresenceofAbndasholigomers(andnM)duringhbQuantificationofSVlevelsintheabsenceorpresenceofNa(nM)NotethatNablockedthereductioninSVinducedbyAboligomersLGAguayoetalagentstomodifythecourseofADAdditionally,thesestudiesshouldprovideanewrationaleforthedevelopmentofdrugsthatblocktheAbporeandpossiblyinterferewithADonsetOurdataindicatesthattheeffectsofAboligomersonintracellularCaplayakeyroleinthealterationsonsynaptictransmissioninducedbythepeptide,whichisinagreementwithpreviousstudiesinvolvingthisdivalentcationonAboligomerseffectsForexample,wefoundthattheeffectsofAboligomersonintracellularcalciumanditsassociatedsynaptictransmissionwerelargelyattenuatedbyreducingtheinfluxofcalciumeitherbyremovalofthiscationorbypharmacologicalmeans(Figsband)Thus,itispossibletoconcludethatthesynapticeffectsofAboligomersarecalciumdependentandabletobemodulatedSeveralquestionsconcerningthemechanismsforAboligomersinsertionandperturbationofneuronalmembranesshouldberesolvedinfuturestudiesForexample,althoughformationofaLTXporesseemstobemostlyindependentofmembranereceptors,somemembraneproteinscouldfacilitateporeinsertionEquivalentmechanismsmaybetruefortheinteractionofAboligomerswithneuronalmembranesStudiesofthefeaturesofaLTXusingcryoelectronmicroscopydemonstratethataLTXpenetratesthecellmembraneandformsporeshavingalargediameter(ndashAring)thatfacilitatesthereleaseofseveralneurotransmitters(eg,norepinephrin,glutamate,andgammaaminobutyricacid)byanonvesiculareffluxmechanismSuchdataisnotavailableforAbinducedpores,bunctionalstudieshaveindicatedthatAbporesareabletocarrydivalentcations,TheinnerdiametersofAbpores,estimatedbyatomicforcemicroscopyandmoleculardynamicsanalysis,,haveasimilarrange(ndashAring)Therefore,theymightpermitthenonvesiculareffluxofseveralmetabolites,generatingimportantchangesinthemetaboliccellularstateBecauseoftheremarkablesimilaritiesinthemechanismofactionbetweentheseporeformingneurotoxinsandAboligomers(Table),wepostulatethataporeformingmechanismmightexplainhowAboligomersinducethesynapticdysfunctionandneurodegenerationinAD(Fig)WeproposethatAboligomersmightalsobindtopostsynapticmembranescausingtheirremodeling,butwithaslowertimecourseTableComparisonbetweenaLTXandAboligomersinducedporesaLTXAbReferencesMWofmonomerkDakDa,Proposednumberofmonomersporesupand,Channelconductance(approximated)Multiplelevels,ndashpSMultiplelevels,ndashpS,EstimatedinnerporediameterndashAringndashAring,MaincationstransportedCa,NaCa,Na,Cs,EffectiveproteinconcentrationndashnMndashnM,Onsetofsynapticactionminmin,Acuteenhancementofvesicularreleaseyesyes,Delayedvesiculardepletionyesyes,PoreFormingNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureConclusionsWearecurrentlystudyingthemechanismsthatcanexplainthechangesinintracellularcalciumandsynaptotoxicityfollowingAboligomersapplicationtobrainneuronsbytesting:()voltagedependentcalciumchannels,()Nmethyldaspartate(NMDA)receptors,and()membraneconductancefollowingAbporeorchannelformationFromthisdata,weexpecttolearnhowAboligomersinhibitssynaptictransmissioninbrainneuronsinvolvedwithlearningandmemory,withtheaimofstoppingorbetterstill,reversingthisprocessThemostinterestingfeatureofAboligomersonsynaptictransmissionisitsbiphasicactionwhichleadstoastrongsynapticfailurethatweinterpretasaprocessofsynapticdepletionInterestingly,whentheearlyeffectsofAboligomerswereblockedwithlowextracellularcalcium,cadmium,orrutheniumred,theneuronsdidnotshowsynapticinhibitionsuggestingthatthedelayedinhibitionwassimilartothesynapticdepletioninducedbyaLTXAccordingtopreviousandpresentevidence,threeprincipalstepsareinvolvedintheneurotoxinlikemechanismfortheactionofAboligomerstoinducetheearlysynapticeffectsneededtotriggerADonsetFirst,Aboligomershavetobindtoneuronalcellmembranes,preandpostsynaptic,longenoughtoensureAbndashAbFigProposedhypothesisthatexplainstheeffectofAboligomersonsynaptictransmissionaAboligomersbindtothemembraneinducingtheformationofporesinthepreandpostsynapticmembranesTheporesallowcalciumtoenterthecellandthiseventcanbeblockedbyNabProposedseriesofeventsthatleadstoADItsinitiationdependsonoligomerizationandmembraneperturbationsthatleadtoacalciumdysfunctionandalterationsinsynaptictransmission(SeeColorPlates)LGAguayoetalinteractionsintothemembraneSecond,AbformsoligomersintothecellmembranetoallowtheformationofaporeThird,asustainedflowofcations(Ca,Na)throughtheAbporesinitiatesthemodificationofsynapticactivity,whichleadstoremodelingsynapticmorphologyWepostulatethatunderstandingtheprecisemechanismforeachofthesestepswillgreatlyfacilitateapharmacologicaltherapyurgentlyneededfortheworldwidepopulationaffectedbyADAcknowledgmentsThisworkwassupportedbyFONDECYTGrantNo,RingofResearchPBCTACT(LGAandCO)WewouldliketothankLaurenAguayoforherrevisionofthemanuscriptReferencesMastersCL,SimmsG,WeinmanNAetal()AmyloidplaquecoreproteininAlzheimerdiseaseandDownsyndromeProcNatlAcadSciUSA:ndashLesneS,KohMT,KotilinekLetal()AspecificamyloidbproteinassemblyinthebrainimpairsmemoryNature:ndashLambertMP,BarlowAK,ChromyBAetal()Diffusible,nonfibrillarligandsderivedfromAbndasharepotentcentralnervoussystemneurotoxinsProcNatlAcadSciUSA:ndashMcLeanCA,ChernyRA,FraserFWetal()SolublepoolofAbamyloidasadeterminantofseverityofneurodegenerationinAlzheimerrsquosdiseaseAnnNeurol:ndashWalshDM,TownsendM,PodlisnyMBetal()Certaininhibitorsofsyntheticamyloidbpeptide(Ab)fibrillogenesisblockoligomerizationofnaturalAbandtherebyrescuelongtermpotentiationJNeurosci:ndashGraceEA,RabinerCA,BusciglioJ()CharacterizationofneuronaldystrophyinducedbyfibrillarAb:implicationsforAlzheimerrsquosdiseaseNeuroscience:ndashMeyerLuehmannM,SpiresJonesTL,PradaCetal()RapidappearanceandlocaltoxicityofAbplaquesinamousemodelofAlzheimerrsquosdiseaseNature:ndashSelkoeDJ()AlzheimerrsquosdiseaseisasynapticfailureScience:ndashKellyBL,VassarR,FerreiraA()AbinduceddynamindepletioninhippocampalneuronsApotentialmechanismforearlycognitivedeclineinAlzheimerdiseaseJBiolChem:ndashSnyderEM,NongY,AlmeidaCGetal()RegulationofNMDAreceptortraffickingbyAbNatNeurosci:ndashHsiaAY,MasliahE,McConlogueLetal()PlaqueindependentdisruptionofneuralcircuitsinAlzheimerrsquosdiseasemousemodelsProcNatlAcadSciUSA:ndashTerryRD,MasliahE,SalmonDPetal()PhysicalbasisofcognitivealterationsinAlzheimerrsquosdisease:synapselossisthemajorcorrelateofcognitiveimpairmentAnnNeurol:ndashYaoPJ()SynapticfrailtyandclathrinmediatedsynapticvesicletraffickinginAlzheimerrsquosdiseaseTrendsNeurosci:ndashMattsonMP()PathwaystowardsandawayfromAlzheimerrsquosdiseaseNature:ndashHarkanyT,AbrahamI,TimmermanWetal()AbneurotoxicityismediatedbyaglutamatetriggeredexcitotoxiccascadeinratnucleusbasalisEurJNeurosci:ndashScraggJL,FearonIM,BoyleJPetal()AlzheimerrsquosamyloidpeptidesmediatehypoxicupregulationofLtypeCachannelsFASEBJ:ndashKaganBL,HirakuraY,AzimovRetal()ThechannelhypothesisofAlzheimerrsquosdisease:currentstatusPeptides:ndashPoreFormingNeurotoxinLikeMechanismforAbOligomerInducedSynapticFailureDurellSR,GuyHR,ArispeNetal()TheoreticalmodelsoftheionchannelstructureofAbproteinBiophysJ:ndashArispeN,RojasE,PollardHB()AlzheimerdiseaseAbproteinformscalciumchannelsinbilayermembranes:blockadebytromethamineandaluminumProcNatlAcadSciUSA:ndashKawaharaM,KurodaY,ArispeNetal()AlzheimerrsquosAb,humanisletamylin,andprionproteinfragmentevokeintracellularfreecalciumelevationsbyacommonmechanisminahypothalamicGnRHneuronalcelllineJBiolChem:ndashKawaharaM,ArispeN,Kuro

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