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ADDLs对NMDA受体跨膜转运及LTP的影响 Introduction: N-methyl-D-asparticacid(NMDA)receptorsareionotropicglutamatereceptorsthatplayacrucialroleinsynaptictransmissioninthebrain.NMDAreceptorsareinvolvedinlong-termpotentiation(LTP),aprocessthatstrengthenssynapticconnectionsandiscriticalforlearningandmemoryformationinthebrain.NMDAreceptorsalsoplayaroleinvariouspathologicalconditionssuchasschizophreniaandAlzheimer'sdisease.Amyloidbeta(Aβ)peptides,whichaccumulateinthebrainsofpeoplewithAlzheimer'sdisease,havebeenshowntointeractwithNMDAreceptorsandinterferewiththeirnormalfunction.Alternatively,solubleAβoligomerscanbindtoNMDAreceptorsinthesynapseandinducetheformationofADDLs(amyloidbeta-deriveddiffusibleligands),whicharetoxictoneuronsandcanleadtosynapticdysfunctionandneuronaldeath.ThisessayreviewstheeffectsofADDLsonNMDAreceptortraffickingandLTP. EffectsofADDLsonNMDAreceptortrafficking: NMDAreceptorsaretransmembraneproteinsthatcompriseaheterotetramerofNR1,NR2,andNR3subunits.ThetraffickingofNMDAreceptorstothesynapticmembraneisamultistepprocessthatinvolvestheproperfolding,assembly,andtransportofthereceptorsubunits.ADDLshavebeenshowntointerferewiththisprocessanddisruptNMDAreceptortraffickinginseveralways. OnemechanismbywhichADDLsaffectNMDAreceptortraffickingisbyalteringthesurfaceexpressionofNR2B-containingreceptors.NR2BisasubunitoftheNMDAreceptorthatisimportantforsynapticplasticityandLTP.StudieshaveshownthatincubationofneuronswithADDLsresultsinadecreaseinthesurfaceexpressionofNR2B-containingNMDAreceptorsandacorrespondingincreaseintheinternalizationofthesereceptors.Thiseffectismediatedbytheactivationofthec-JunN-terminalkinase(JNK)signalingpathway,whichphosphorylatesNR2Bandpromotesitsinternalization.ThelossofsurfaceNR2B-containingNMDAreceptorscanimpairsynaptictransmissionandcontributetothesynapticdysfunctionassociatedwithAlzheimer'sdisease. AnotherwayinwhichADDLsaffectNMDAreceptortraffickingisbyalteringthedistributionofreceptorswithinthesynapse.NMDAreceptorsaretypicallyclusteredatthepostsynapticde