Abeta42-Induced Neurodegeneration via an Age-Dependent Autophagic-Lysosomal Injury in Drosophila 英文参考文献.docVIP

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Abeta42-Induced Neurodegeneration via an Age-Dependent Autophagic-Lysosomal Injury in Drosophila 英文参考文献.doc

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Abeta42-Induced Neurodegeneration via an Age-Dependent Autophagic-Lysosomal Injury in Drosophila 英文参考文献

Abeta42-InducedNeurodegenerationviaanAge- DependentAutophagic-LysosomalInjuryinDrosophila DaijunLing1,Ho-JuhnSong3,DanGarza3,ThomasP.Neufeld4,PaulM.Salvaterra1,2* 1DivisionofNeuroscience,BeckmanResearchInstituteoftheCityofHope,Duarte,California,UnitedStatesofAmerica,2GraduateSchoolofBiologicalScience,Beckman Research Institute of the City of Hope, Duarte, California, United States of America, 3Department of Developmental and Molecular Pathway, Novartis Institute for BiomedicalResearch,Cambridge,Massachusetts,UnitedStatesofAmerica,4DepartmentofGenetics,UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesof America Abstract ThemechanismofwidespreadneuronaldeathoccurringinAlzheimer’sdisease(AD)remainsenigmaticevenafterextensive investigation during the last two decades. Amyloid beta 42 peptide (Ab1–42) is believed to play a causative role in the developmentofAD.HereweexpressedhumanAb1–42andamyloidbeta40(Ab1–40)inDrosophilaneurons.Ab1–42butnotAb1– 40causesanextensiveaccumulationofautophagicvesiclesthatbecomeincreasinglydysfunctionalwithage.Ab1–42-induced impairmentofthedegradativefunction,aswellasthestructuralintegrity,ofpost-lysosomalautophagicvesiclestriggersa neurodegenerative cascade that can be enhanced by autophagy activation or partially rescued by autophagy inhibition. Compromiseandleakagefrompost-lysosomalvesiclesresultincytosolicacidification,additionaldamagetomembranesand organelles,anderosivedestructionofcytoplasmleadingtoeventualneurondeath.Neuronalautophagyinitiallyappearsto playapro-survivalrolethatchangesinanage-dependentwaytoapro-deathroleinthecontextofAb1–42expression.Ourin vivoobservationsprovideamechanisticunderstandingforthedifferentialneurotoxicityofAb1–42andAb1–40,andrevealan Ab1–42-induceddeathexecutionpathwaymediatedbyanage-dependentautophagic-lysosomalinjury. Citation:LingD,SongH-J,GarzaD,NeufeldTP,SalvaterraPM(2009)Abeta42-InducedNeurodegenerationviaanAge-DependentAutophagic-LysosomalInjury inDrosophila.PLoSONE4(1):e4201.doi:10.1371/jour