APP Knockout Mice Experience Acute Mortality as the Result of Ischemia 英文参考文献.docVIP

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APP Knockout Mice Experience Acute Mortality as the Result of Ischemia 英文参考文献.doc

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APP Knockout Mice Experience Acute Mortality as the Result of Ischemia 英文参考文献

APPKnockoutMiceExperienceAcuteMortalityasthe ResultofIschemia MayaA.Koike1,AlexanderJ.Lin1,2,3,JonathanPham2,3,ElaineNguyen2,JamesJ.Yeh2, RombodRahimian2,BruceJ.Tromberg2,3,BernardChoi2,3,4,KimN.Green1*,FrankM.LaFerla1* 1InstituteforMemoryImpairmentsandNeurologicalDisorders,UniversityofCaliforniaIrvine,Irvine,California,UnitedStatesofAmerica,2LaserMicrobeamandMedical Program,BeckmanLaserInstituteandMedicalClinic,Irvine,California,UnitedStatesofAmerica,3DepartmentofBiomedicalEngineering,UniversityofCaliforniaIrvine, Irvine,California,UnitedStatesofAmerica,4EdwardsLifesciencesCenterforAdvancedCardiovascularTechnology,UniversityofCaliforniaIrvine,Irvine,California,United StatesofAmerica Abstract TheincidenceofAlzheimer’sdiseaseincreasesinpeoplewhohavehadanischemicepisode.Furthermore,APPexpressionis increasedfollowingischemicorhypoxicconditions,asistheproductionoftheAbpeptide.Toaddressthequestionofwhy APP and Ab are increased in hypoxic and ischemic conditions we induced an ischemic episode in APP knockout mice (APP2/2) and BACE1 knockout mice (BACE2/2). We find that both APP2/2 and BACE2/2 mice have a dramatically increasedriskofmortalityasaresultofcerebralischemia.Furthermore,APPknockoutmicehavereducedcerebralblood flow in response to hypoxia, while wild-type mice maintain or increase cerebral blood flow to the sameconditions. The transcription factor, serum response factor (SRF), and calcium-binding molecule, calsequestrin, both involved in vascular regulation,aresignificantlyalteredinthebrainsofAPP2/2micecomparedtowildtypecontrols.Theseresultsshowthat APP regulates cerebral blood flow in response to hypoxia, and that it, and its cleavage fragments, are crucial for rapid adaptationtoischemicconditions. Citation: Koike MA,LinAJ,PhamJ,NguyenE,Yeh JJ,etal.(2012)APP KnockoutMiceExperienceAcute Mortality astheResultofIschemia.PLoS ONE7(8): e42665.doi:10.1371/journal.pone.0042665 Editor:SimoneDiGiovanni,HertieInstituteforClinicalBrainResearch,UniversityofTuebinge