Regulation of Neuronal APL-1 Expression by Cholesterol Starvation 英文参考文献.docVIP

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Regulation of Neuronal APL-1 Expression by Cholesterol Starvation 英文参考文献.doc

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Regulation of Neuronal APL-1 Expression by Cholesterol Starvation 英文参考文献

RegulationofNeuronalAPL-1ExpressionbyCholesterol Starvation MaryWiese1,AdamAntebi1,2*,HuiZheng1* 1HuffingtonCenteronAgingandDepartmentofMolecularandHumanGenetics,BaylorCollegeofMedicine,Houston,Texas,UnitedStatesofAmerica,2MaxPlanck InstituteforBiologyofAgeing,Ko¨ln,Germany Abstract Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the deposition of b-amyloid plaques composed primarily of the amyloid-b peptide, a cleavage product of amyloid precursor protein (APP). While mutationsinAPPleadtothedevelopmentofFamilialAlzheimer’sDisease(FAD),sporadicADhasonlyonecleargenetic modifier:thee4alleleoftheapolipoproteinE(ApoE)gene.CholesterolstarvationinCaenorhabditiselegansleadstomolting andarrestphenotypessimilartoloss-of-functionmutantsoftheAPPortholog,apl-1(amyloidprecursor-likeprotein1),and lrp-1(lipoproteinreceptor-relatedprotein1),suggestingapotentialinteractionbetweenapl-1andcholesterolmetabolism. Methodology/Principal Findings:Previously,wefoundthatRNAiknock-downofapl-1leadstoaldicarbhypersensitivity, indicating a defect in synaptic function. Here we find the same defect is recapitulated during lrp-1 knock-down and by cholesterolstarvation.Acholesterol-freedietorlossoflrp-1directlyaffectsAPL-1levelsasbothleadtolossofAPL-1::GFP fluorescenceinneurons.However,lossofcholesteroldoesnotaffectglobaltranscriptionorproteinlevelsasseenbyqPCR andWesternblot. Conclusions:Ourresultsshowthatcholesterolandlrp-1areinvolvedintheregulationofsynaptictransmission,similarto apl-1.BothareabletomodulateAPL-1proteinlevelsinneurons,howevercholesterolchangesdonotaffectglobalapl-1 transcriptionorAPL-1proteinindicatingthechangesarespecifictoneurons.Thus,regulationofsynaptictransmissionand moltingbyLRP-1andcholesterolmaybemediatedbytheirabilitytocontrolAPL-1neuronalproteinexpression. Citation: Wiese M, Antebi A, Zheng H (2012) Regulation of Neuronal APL-1 Expression by Cholesterol Starvation. PLoS ONE 7(2): e32038. doi:10.1371/ journal.pone.0032038 Editor:Hua