Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells Binding and Growth at Physiological Concentrations 英文参考文献.docVIP

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Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells Binding and Growth at Physiological Concentrations 英文参考文献.doc

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Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells Binding and Growth at Physiological Concentrations 英文参考文献

DirectObservationofSingleAmyloid-b(1-40)Oligomers onLiveCells:BindingandGrowthatPhysiological Concentrations RobinD.Johnson1*,JosephA.Schauerte1,KathleenC.Wisser1,AriGafni1,2,DuncanG.Steel1,3,4 1DepartmentofBiophysics,TheUniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,2DepartmentofBiologicalChemistry,TheUniversityofMichigan, AnnArbor,Michigan,UnitedStatesofAmerica,3DepartmentofPhysics,TheUniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,4Departmentof ElectricalEngineeringandComputerScience,TheUniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica Abstract Understandinghowamyloid-bpeptideinteractswithlivingcellsonamolecularleveliscriticaltodevelopmentoftargeted treatmentsforAlzheimer’sdisease.EvidencethatoligomericAbinteractswithneuronalcellmembraneshasbeenprovided, butthemechanismbywhichmembranebindingoccursandtheexactstoichiometryoftheneurotoxicaggregatesremain elusive.PhysiologicallyrelevantexperimentationishinderedbythehighAbconcentrationsrequiredformostbiochemical analyses, the metastable nature of Ab aggregates, and the complex variety of Ab species present under physiological conditions.Hereweusesinglemoleculemicroscopytoovercomethesechallenges,presentingdirectopticalevidencethat smallAb(1-40)oligomersbindtolivingneuroblastomacellsatphysiologicalAbconcentrations.Singleparticlefluorescence intensitymeasurementsindicatethatcell-boundAbspeciesrangeinsizefrommonomerstohexamersandgreater,withthe majorityofboundoligomersfallinginthedimer-to-tetramerrange.Furthermore,whilelow-molecularweightoligomeric speciesdoforminsolution,themembrane-boundoligomersizedistributionisshiftedtowardslargeraggregates,indicating either that bound Ab oligomers can rapidly increase in size or that these oligomers cluster at specific sites on the membrane.Calciumindicatorstudiesdemonstratethatsmalloligomerbindingatphysiologicalconcentrationsinducesonly mild,sporadiccalciumleakage.ThesefindingssupportthehypothesisthatsmalloligomersaretheprimaryAbspeciesthat in