Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment 英文参考文献.docVIP

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Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment 英文参考文献.doc

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Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment 英文参考文献

SmallMolecule,Non-Peptidep75NTR LigandsInhibitAb- InducedNeurodegenerationandSynapticImpairment TaoYang1,2.,JulietK.Knowles1,2.,QunLu3,HongZhang4,OttavioArancio4,LauraA.Moore2 ,Timothy Chang1,QianWang1,KatrinAndreasson1,JayakumarRajadas1,5,GeraldG.Fuller5,YoumeiXie2, StephenM.Massa6,FrankM.Longo1,2* 1DepartmentofNeurologyandNeurologicalScience,StanfordUniversity,Stanford,California,UnitedStatesofAmerica,2DepartmentofNeurology,UniversityofNorth Carolina-ChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica, 3DepartmentofAnatomyandCellBiology,TheBrodySchoolofMedicineatEastCarolina University,Greenville,NorthCarolina,UnitedStatesofAmerica,4DepartmentofPathologyandTaubInstitute,ColumbiaUniversity,NewYork,NewYork,UnitedStatesof America, 5Department of Chemical Engineering, Stanford University, Stanford, California, United States of America, 6Department of Neurology and Laboratory for ComputationalNeurochemistryandDrugDiscovery,SanFranciscoVeteransAffairsMedicalCenter,andDepartmentofNeurology,UniversityofCaliforniaSanFrancisco, SanFrancisco,California,UnitedStatesofAmerica Abstract Thep75neurotrophinreceptor(p75NTR)isexpressedbyneuronsparticularlyvulnerableinAlzheimer’sdisease(AD).Wetested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Ab- induceddegenerationandsynapticdysfunction.TheseligandsinhibitedAb-inducedneuriticdystrophy,deathofcultured neuronsandAb-induceddeathofpyramidalneuronsinhippocampalslicecultures.Moreover,ligandsinhibitedAb-induced activationofmoleculesinvolvedinADpathologyincludingcalpain/cdk5,GSK3bandc-Jun,andtauphosphorylation,and prevented Ab-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Ab-induced hippocampal LTP impairment.Thesestudiessupportanextensiveintersectionbetweenp75NTRsignalingandAbpathogenicmechanisms,and introduceaclassofspecificsmallmoleculeligandswiththeuniqueabilitytoblockmultiplefundamentalAD-relatedsignaling pathways,reversesynaptic