Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele 英文参考文献.docVIP

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Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele 英文参考文献.doc

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Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele 英文参考文献

DisruptionofArterialPerivascularDrainageofAmyloid- bfromtheBrainsofMiceExpressingtheHumanAPOEe4 Allele CherylA.Hawkes1,PatrickM.Sullivan2,SarahHands3,RoyO.Weller1,JamesA.R.Nicoll1, RoxanaO.Carare1* 1ClinicalNeurosciences,ClinicalandExperimentalSciences,FacultyofMedicine,UniversityofSouthampton,Southampton,UnitedKingdom,2DepartmentofMedicine, DukeUniversity,DurhamVAMedicalCenterandGRECC,Durham,NorthCarolina,UnitedStatesofAmerica,3FacultyofNaturalandEnvironmentalSciences,Universityof Southampton,Southampton,UnitedKingdom Abstract Failureofeliminationofamyloid-b(Ab)fromthebrainandvasculatureappearstobeakeyfactorintheetiologyofsporadic Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE)e4alleleisastrongriskfactorforthedevelopmentofsporadicAD.Thepresentstudytestedthehypothesisthat possession of the APOE e4 allele is associated with disruption of perivascular drainage of Ab from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3(TRE3)orAPOE4(TRE4)genesandwildtypemicereceivedintracerebralinjectionsofhumanAb40.Ab40aggregatedin peri-arterialdrainagepathwaysinTRE4mice,butnotinTRE3orwildtypemice.ThenumberofAbdepositswassignificantly higherinthehippocampiofTRE4micethanintheTRE3mice,atboth3-and16-monthsofage,suggestingthatclearanceof Ab was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membraneproteinsdemonstratedsignificantlyraisedlevelsofcollagenIVin3-month-oldTRE4micecomparedwithTRE3 andwildtypemice.In16-month-oldmice,collagenIVandlamininlevelswereunchanged betweenwildtypeandTRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruptionandimpedanceofperivasculardrainageofsolubleAbfromthebrain.Thiseffectmaybemediated,inpart,by changesinage-relatedexpressionofbasementmembraneproteinsint