β甘油磷酸二钠水合物

β淀粉样肽1-40C端抗体

ThecerebralandvascularplaquesassociatedwithAlzheimer'sdiseasearemainlycomposedofAmyloidbetapeptides.betaAmyloidisderivedfromcleavageoftheAmyloidprecursorproteinandvariesinlengthfrom39to43aminoacids.betaAmyloid[1-40],betaAmyloid[1-42],andbetaAmyloid[1-43]peptidesresultfromcleavageofAmyloidprecursorproteinafterresidues40,42,and43,respectively.Thecleavagetakesplacebygamma-secretaseduringthelastAmyloidprecursorproteinprocessingstep.betaAmyloid[1-40],betaAmyloid[1-42],andbetaAmyloid[1-43]peptidesaremajorconstituentsoftheplaquesandtanglesthatoccurinAlzheimer'sdisease.betaAmyloidantibodiesandpeptideshavebeendevelopedastoolsforelucidatingthebiologyofAlzheimer'sdisease.
Function:Functionsasacellsurfacereceptorandperformsphysiologicalfunctionsonthesurfaceofneuronsrelevanttoneuritegrowth,neuronaladhesionandaxonogenesis.Involvedincellmobilityandtranscriptionregulationthroughprotein-proteininteractions.CanpromotetranscriptionactivationthroughbindingtoAPBB1-KAT5andinhibitsNotchsignalingthroughinteractionwithNumb.Couplestoapoptosis-inducingpathwayssuchasthosemediatedbyG(O)andJIP.InhibitsG(o)alphaATPaseactivity.ActsasakinesinImembranereceptor,mediatingtheaxonaltransportofbeta-secretaseandpresenilin1.Involvedincopperhomeostasis/oxidativestressthroughcopperionreduction.Invitro,copper-metallatedAPPinducesneuronaldeathdirectlyorispotentiatedthroughCu(2+)-mediatedlow-densitylipoproteinoxidation.CanregulateneuriteoutgrowththroughbindingtocomponentsoftheextracellularmatrixsuchasheparinandcollagenIandIV.ThespliceisoformsthatcontaintheBPTIdomainpossessproteaseinhibitoractivity.InducesaAGER-dependentpathwaythatinvolvesactivationofp38MAPK,resultingininternalizationofamyloid-betapeptideandleadingtomitochondrialdysfunctioninculturedcorticalneurons.
Beta-amyloidpeptidesarelipophilicmetalchelatorswithmetal-reducingactivity.Bindtransientmetalssuchascopper,zincandiron.Invitro,canreduceCu(2+)andFe(3+)toCu(+)andFe(2+),respectively.Beta-amyloid42isamoreeffectivereductantthanbeta-amyloid40.Beta-amyloidpeptidesbindtolipoproteinsandapolipoproteinsEandJintheCSFandtoHDLparticlesinplasma,inhibitingmetal-catalyzedoxidationoflipoproteins.Beta-APP42mayactivatemononuclearphagocytesinthebrainandelicitinflammatoryresponses.PromotesbothtauaggregationandTPKII-mediatedphosphorylation.InteractionwithoverexpressedHADH2leadstooxidativestressandneurotoxicity.
Appicanselicitadhesionofneuralcellstotheextracellularmatrixandmayregulateneuriteoutgrowthinthebrai.
Thegamma-CTFpeptidesaswellasthecaspase-cleavedpeptides,includingC31,arepotentenhancersofneuronalapoptosis.
N-APPbindsTNFRSF21triggeringcaspaseactivationanddegenerationofbothneuronalcellbodies(viacaspase-3)andaxons(viacaspase-6).
Subunit:Binds,viaitsC-terminus,tothePIDdomainofseveralcytoplasmicproteins,includingAPBBfamilymembers,theAPBAfamily,MAPK8IP1,SHC1and,NUMBandDAB.BindingtoDAB1inhibitsitsserinephosphorylation(Bysimilarity).AlsointeractswithGPCR-likeproteinBPP,FPRL1,APPBP1,IB1,KNS2(viaitsTPRdomains),APPBP2(viaBaSS)andDDB1.Invitro,itbindsMAPTviatheMT-bindingdomains.AssociateswithmicrotubulesinthepresenceofATPandinakinesin-dependentmanner.Interacts,throughaC-terminaldomain,withGNAO1.Amyloidbeta-42bindsCHRNA7inhippocampalneurons.Beta-amyloidassociateswithHADH2.SolubleAPPbinds,viaitsN-terminalhead,toFBLN1.InteractswithCPEB1andAGER.InteractswithANKS1BandTNFRSF21.InteractswithITM2B.InteractswithITM2C.InteractswithIDE.Canformhomodimers;thisispromotedbyheparinbinding.
SubcellularLocation:Membrane;Single-passtypeImembraneprotein.Membrane,clathrin-coatedpit.Note=Cellsurfaceproteinthatrapidlybecomesinternalizedviaclathrin-coatedpits.Duringmaturation,theimmatureAPP(N-glycosylatedintheendoplasmicreticulum)movestotheGolgicomplexwherecompletematurationoccurs(O-glycosylatedandsulfated).Afteralpha-secretasecleavage,solubleAPPisreleasedintotheextracellularspaceandtheC-terminalisinternalizedtoendosomesandlysosomes.SomeAPPaccumulatesinsecretorytransportvesiclesleavingthelateGolgicompartmentandreturnstothecellsurface.Gamma-CTF(59)peptideislocatedtoboththecytoplasmandnucleiofneurons.ItcanbetranslocatedtothenucleusthroughassociationwithAPBB1(Fe65).Beta-APP42associateswithFRPL1atthecellsurfaceandthecomplexisthenrapidlyinternalized.APPsortstothebasolateralsurfaceinepithelialcells.Duringneuronaldifferentiation,theThr-743phosphorylatedformislocatedmainlyingrowthcones,moderatelyinneuritesandsparinglyinthecellbody.Caseinkinasephosphorylationcanoccureitheratthecellsurfaceorwithinapost-Golgicompartment.
TissueSpecificity:Expressedinallfetaltissuesexaminedwithhighestlevelsinbrain,kidney,heartandspleen.Weakexpressioninliver.Inadultbrain,highestexpressionfoundinthefrontallobeofthecortexandintheanteriorperisylviancortex-operculargyri.Moderateexpressioninthecerebellarcortex,theposteriorperisylviancortex-operculargyriandthetemporalassociatedcortex.Weakexpressionfoundinthestriate,extra-striateandmotorcortices.Expressedincerebrospinalfluid,andplasma.IsoformAPP695isthepredominantforminneuronaltissue,isoformAPP751andisoformAPP770arewidelyexpressedinnon-neuronalcells.IsoformAPP751isthemostabundantforminT-lymphocytes.Appicanisexpressedinastrocytes.
Post-translationalmodifications:Proteolyticallyprocessedundernormalcellularconditions.Cleavageeitherbyalpha-secretase,beta-secretaseortheta-secretaseleadstogenerationandextracellularreleaseofsolubleAPPpeptides,S-APP-alphaandS-APP-beta,andtheretentionofcorrespondingmembrane-anchoredC-terminalfragments,C80,C83andC99.SubsequentprocessingofC80andC83bygamma-secretaseyieldsP3peptides.Thisisthemajorsecretorypathwayandisnon-amyloidogenic.Alternatively,presenilin/nicastrin-mediatedgamma-secretaseprocessingofC99releasestheamyloidbetaproteins,amyloid-beta40(Abeta40)andamyloid-beta42(Abeta42),majorcomponentsofamyloidplaques,andthecytotoxicC-terminalfragments,gamma-CTF(50),gamma-CTF(57)andgamma-CTF(59).
Proteolyticallycleavedbycaspasesduringneuronalapoptosis.CleavageatAsp-739byeithercaspase-6,-8or-9resultsintheproductionoftheneurotoxicC31peptideandtheincreasedproductionofbeta-amyloidpeptides.
N-andO-glycosylated.O-linkageofchondroitinsulfatetotheL-APPisoformsproducestheAPPproteoglycancoreproteins,theappicans.Thechondroitinsulfatechainofappicanscontains4-O-sulfatedgalactoseinthelinkageregionandchondroitinsulfateEintherepeateddisaccharideregion.
PhosphorylationintheC-terminalontyrosine,threonineandserineresiduesisneuron-specific.PhosphorylationcanaffectAPPprocessing,neuronaldifferentiationandinteractionwithotherproteins.PhosphorylatedonThr-743inneuronalcellsbyCdc5kinaseandMapk10,individingcellsbyCdc2kinaseinacell-cycledependentmannerwithmaximallevelsattheG2/Mphaseand,invitro,byGSK-3-beta.TheThr-743phosphorylatedformcausesaconformationalchangewhichreducesbindingofFe65familymembers.PhosphorylationonTyr-757isrequiredforSHCbinding.Phosphorylatedintheextracellulardomainbycaseinkinasesonbothsolubleandmembrane-boundAPP.Thisphosphorylationisinhibitedbyheparin.
Extracellularbindingandreductionofcopper,resultsinacorrespondingoxidationofCys-144andCys-158,andtheformationofadisulfidebond.Invitro,theAPP-Cu(+)complexinthepresenceofhydrogenperoxideresultsinanincreasedproductionofbeta-amyloid-containingpeptides.
Trophic-factordeprivationtriggersthecleavageofsurfaceAPPbybeta-secretasetoreleasesAPP-betawhichisfurthercleavedtoreleaseanN-terminalfragmentofAPP(N-APP).Beta-amyloidpeptidesaredegradedbyIDE.
DISEASE:DefectsinAPParethecauseofAlzheimerdiseasetype1(AD1)[MIM:104300].AD1isafamilialearly-onsetformofAlzheimerdisease.Itcanbeassociatedwithcerebralamyloidangiopathy.Alzheimerdiseaseisaneurodegenerativedisordercharacterizedbyprogressivedementia,lossofcognitiveabilities,anddepositionoffibrillaramyloidproteinsasintraneuronalneurofibrillarytangles,extracellularamyloidplaquesandvascularamyloiddeposits.Themajorconstituentoftheseplaquesistheneurotoxicamyloid-beta-APP40-42peptide(s),derivedproteolyticallyfromthetransmembraneprecursorproteinAPPbysequentialsecretaseprocessing.ThecytotoxicC-terminalfragments(CTFs)andthecaspase-cleavedproductssuchasC31derivedfromAPP,arealsoimplicatedinneuronaldeath.
DefectsinAPParethecauseofcerebralamyloidangiopathyAPP-related(CAA-APP)[MIM:605714].Ahereditarylocalizedamyloidosisduetoamyloid-betaA4peptide也称βA4蛋白，是β-淀粉样蛋白前体（APP）经β和γ分泌酶分解后的产物，有39-43个氨基酸残基组成。是淀粉样蛋白的主要成分。
β-淀粉样蛋白来自β-淀粉样蛋白原，在脑组织的细胞外呈丝状蛋白样沉积，是淀粉样结节性神经炎病变的主要蛋白成分，在神经纤维中也有沉积。