Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimers Disease 英文参考文献.docVIP

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Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimers Disease 英文参考文献.doc

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Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimers Disease 英文参考文献

DysregulationofthemTORPathwayMediates ImpairmentofSynapticPlasticityinaMouseModelof Alzheimer’sDisease TaoMa1,CharlesA.Hoeffer2,EstibalizCapetillo-Zarate1,FangminYu1,HelenWong2,MichaelT.Lin1, DavideTampellini1,EricKlann2,RobertD.Blitzer3,GunnarK.Gouras1,4* 1Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, United States of America, 2Center for Neural Science, New York University,NewYork,NewYork,UnitedStatesofAmerica,3DepartmentofPharmacologyandSystemsTherapeutics,MountSinaiSchoolofMedicine,NewYork,New York,UnitedStatesofAmerica,4RockefellerUniversity,NewYork,NewYork,UnitedStatesofAmerica Abstract Background:Themammaliantargetofrapamycin(mTOR)isanevolutionarilyconservedSer/Thrproteinkinasethatplaysa pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and b-amyloid (Ab)-induced synaptic dysfunction, which is considered to be critical in the pathogenesisofAlzheimer’sdisease(AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synapticplasticityinhippocampalslicesfromanADmousemodelandinwild-typeslicesexposedtoexogenousAb1-42. Importantly,byup-regulatingmTORsignaling,glycogensynthasekinase3(GSK3)inhibitorsrescuedLTPintheADmouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Ab-induced impairment in long-term potentiation(LTP).Inaddition,confocalmicroscopydemonstratedco-localizationofintraneuronalAb42withmTOR. Conclusions/Significance:ThesedatasupportthenotionthatthemTORpathwaymodulatesAb-relatedsynapticdysfunction inAD. Citation:MaT,HoefferCA,Capetillo-ZarateE,YuF,WongH,etal.(2010)DysregulationofthemTORPathwayMediatesImpairmentofSynapticPlasticityina MouseModelofAlzheimer’sDisease.PLoSONE5(9):e12845.doi:10.1371/journal.pone.0012845 Editor:MelB.Feany,BrighamandWomen’sHospital,HarvardMedicalSchool,UnitedStatesofAmerica ReceivedJune9,2010;Accept