Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice

International Journal of Physiology, Pathophysiology and Pharmacology

Elliott J Mufson¹  Katherine R Sadleir¹  Joanna Matras¹  Sylvia E Perez¹  Muhammad Nadeem¹  Christy M Kelley¹  Scott E Counts¹  Robert Vassar¹ 

[1] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

关键词: Alzheimer’s disease;    amyloid;    dimebon;    hippocampus;    plaques;    tangles;    tau;    transgenic mice;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Adoubleblind,placebo-controlledphaseIIstudyrevealedthattheantihistamine,Dimebon#174;(dimebolin,latrepirdine)improvedcognitioninAlzheimerdisease(AD)patientscomparedtoplacebocontrols.However,thePhaseIIICONNECTIONtrialfailedtodemonstratesignificantdifferencesbetweendimebonandplacebotreatments.DespitethecontroversialtherapeuticoutcomesinthetreatmentofAD,dimebon#8217;smechanism(s)ofactionwithinthebrainremainunclear.Inthepresentstudy,weevaluatedtheeffectsofdimebonupon#946;-amyloid(A#946;),tauandastrocytesinthehippocampusoftripletransgenic(3xTg-AD)mice,whichdevelopAD-likepathologyinanage-dependentmanner.Atage6.5months,priortothedevelopmentofA#946;plaquesinthehippocampus,maleandfemale3xTg-ADmice,receivedadailyintraperitonealinjectionof0.1%dimebonorsalinefor1.5months.At8months,quantitativeimmunohistochemistryrevealedasignificantreductioninhippocampal/subicularAPP/A#946;indimebon-treatedmice,whereasproteinbioassayfoundnochangeinfulllengthAPP,solubleA#946;1-40andA#946;1-42,A#946;oligomers,BACE1andGFAPlevelsbetweengroups.Interestingly,thenumberofthehippocampalAPP/A#946;plaquesinfemaleandmaledimebon-treatedmicewashighercomparedtogender-matchedcontrolmice.Dimebondidnotalterhippocampaltaulevels.Furthermore,dimebonprotectsSH-SY5YneuronsagainstA#946;toxicityandpromotesGFAPexpressioninprimarymouseastrocytecultures.OurfindingsdemonstratethatdimeboninvivomodifieshippocampalAPP/A#946;pathologyandinvitroprotectsagainstA#946;toxicitypromotingcellsurvivalandactivatesastrocytes.(IJPPP1208006).

【 授权许可】

Unknown