Reversal of Fragile X Phenotypes by Manipulation of AβPPAβ Levels in Fmr1KO Mice 英文参考文献.docVIP

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Reversal of Fragile X Phenotypes by Manipulation of AβPPAβ Levels in Fmr1KO Mice 英文参考文献.doc

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Reversal of Fragile X Phenotypes by Manipulation of AβPPAβ Levels in Fmr1KO Mice 英文参考文献

ReversalofFragileXPhenotypesbyManipulationof AbPP/AbLevelsinFmr1KO Mice CaraJ.Westmark1*,PamelaR.Westmark1,KennethJ.O’Riordan2,BrianC.Ray1,CrystalM.Hervey4 ,M. ShahriarSalamat3,SaraH.Abozeid1,KelseyM.Stein1,LeviA.Stodola1,MichaelTranfaglia7 ,Corinna Burger2,ElizabethM.Berry-Kravis4,5,6,JamesS.Malter1,3¤ 1Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America, 2Department of Neurology, University of Wisconsin,Madison,Wisconsin,UnitedStatesofAmerica,3DepartmentofPathologyLaboratoryMedicine,UniversityofWisconsin,Madison,Wisconsin,UnitedStatesof America,4DepartmentofPediatrics,RushUniversityMedicalCenter,Chicago,Illinois,UnitedStatesofAmerica,5DepartmentofBiochemistry,RushUniversityMedical Center, Chicago, Illinois, United States ofAmerica, 6Department ofNeurological Sciences, Rush UniversityMedicalCenter, Chicago, Illinois, United States ofAmerica, 7FRAXAResearchFoundation,Newburyport,Massachusetts,UnitedStatesofAmerica Abstract FragileXsyndrome(FXS)isthemostcommonformofinheritedintellectualdisabilityandtheleadingknowngeneticcause ofautism.FragileXmentalretardationprotein(FMRP),whichisabsentorexpressedatsubstantiallyreducedlevelsinFXS, binds to and controls the postsynaptic translation of amyloid b-protein precursor (AbPP) mRNA. Cleavage of AbPP can produceb-amyloid(Ab),a39–43aminoacidpeptidemis-expressedinAlzheimer’sdisease(AD)andDownsyndrome(DS). Abisover-expressedinthebrainofFmr1KOmice,suggestingapathogenicroleinFXS.Todetermineifgeneticreductionof AbPP/AbrescuescharacteristicFXSphenotypes,weassessedaudiogenicseizures(AGS),anxiety,theratioofmatureversus immaturedendriticspinesandmetabotropicglutamatereceptor(mGluR)-mediatedlong-termdepression(LTD)inFmr1KO miceafterremovalofoneAppallele.Allofthesephenotypeswerepartiallyorcompletelyrevertedtonormal.PlasmaAb1–42 wassignificantly reducedinfull-mutationFXS malescomparedtoage-matched controlswhilecortical andhippocampal levelsweresomewhatincreased,suggest