Sodiummyo-Inositol Transporters Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology 英文参考文献.docVIP

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Sodiummyo-Inositol Transporters Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology 英文参考文献.doc

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Sodiummyo-Inositol Transporters Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology 英文参考文献

Sodium/myo-InositolTransporters:SubstrateTransport RequirementsandRegionalBrainExpressioninthe TgCRND8MouseModelofAmyloidPathology DanielaFenili1,Ying-QiWeng2,IsabelleAubert1,2,MarkNitz3,JoAnneMcLaurin1* 1DepartmentofLaboratoryMedicineandPathobiology,UniversityofToronto,Toronto,Ontario,Canada,2BrainSciences,SunnybrookResearchInstitute,Universityof Toronto,Toronto,Ontario,Canada,3DepartmentofChemistry,UniversityofToronto,Toronto,Ontario,Canada Abstract Inositolstereoisomers,myo-andscyllo-inositol,areknowntoenterthebrainandaresignificantlyelevatedfollowingoral administration.Elevationsinbraininositollevelsoccuracrossaconcentrationgradientasaresultofactivetransportfrom theperiphery.Therearetwosodium/myo-inositoltransporters(SMIT1,SMIT2)thatmayberesponsibleforregulatingbrain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer’s disease (AD)-like amyloid pathologyontransporterexpression,tocompareregionalexpressionandtoanalyzesubstraterequirementsoftheinositol transporters.QPCRwasusedtoexamineexpressionofthetwotransportersinthecortex,hippocampusandcerebellumof TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined thestructural features ofinositol required for active transport, utilizing acell-based competitiveuptake assay. Diseasepathologydidnotaltertransporterexpressioninthecortexorhippocampus(p.0.005),withonlyminimaleffectsof agingobservedinthecerebellum(SMIT1:F2,26=12.62;p=0.0002;SMIT2:F2,26=8.71;p=0.0015).Overall,brainSMIT1levels werehigherthanSMIT2,however,regionaldifferenceswereobserved.ForSMIT1,at4and6monthscerebellarSMIT1levels were significantly higher than cortical and hippocampal levels (p,0.05). For SMIT2, at all three ages both cortical and cerebellarSMIT2levelsweresignificantlyhigherthanhippocampallevels(p,0.05)andat4and6monthsofage,cerebellar SMIT2levelswerealsosignificantlyhigherthancorticallevels(p,0.05).Inositoltransporterlevelsarestablyexpressed