2023
Neuronal transcriptome, tau and synapse loss in Alzheimer’s knock-in mice require prion protein
Stoner A, Fu L, Nicholson L, Zheng C, Toyonaga T, Spurrier J, Laird W, Cai Z, Strittmatter S. Neuronal transcriptome, tau and synapse loss in Alzheimer’s knock-in mice require prion protein. Alzheimer's Research & Therapy 2023, 15: 201. PMID: 37968719, PMCID: PMC10647125, DOI: 10.1186/s13195-023-01345-z.Peer-Reviewed Original ResearchConceptsSynapse lossDKI miceTau accumulationBrain immune activationNeural network dysfunctionPhospho-tau accumulationAccumulation of tauNeuronal genesInflammatory markersAD miceAβ levelsPrion proteinDystrophic neuritesImmune activationTau pathologyNeuronal gene expressionAmyloid-β OligomersGliotic reactionNetwork dysfunctionBehavioral deficitsSynaptic failureAD modelMemory impairmentAlzheimer's diseaseFunction of ageConcerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions
de Arce K, Ribic A, Chowdhury D, Watters K, Thompson G, Sanganahalli B, Lippard E, Rohlmann A, Strittmatter S, Missler M, Hyder F, Biederer T. Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions. Nature Communications 2023, 14: 459. PMID: 36709330, PMCID: PMC9884278, DOI: 10.1038/s41467-023-36042-w.Peer-Reviewed Original ResearchConceptsPrefrontal cortexDKO miceSynCAM 1Aberrant neuronal activityDendritic spine numberPrefrontal cortex synapsesSynapse organizersSynapse numberMature brainNeuronal activityKnockout miceSpine numberSynapse developmentCognitive functionTrans-synaptic complexesImmunoglobulin family membersMiceFamily membersSynapsesLRRTM1Behavioral domainsHippocampusCognitive tasksConcerted roleCortex
2022
Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q
Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Pérez-Cañamás A, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Cai Z, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Science Translational Medicine 2022, 14: eabi8593. PMID: 35648810, PMCID: PMC9554345, DOI: 10.1126/scitranslmed.abi8593.Peer-Reviewed Original ResearchConceptsPositron emission tomographySilent allosteric modulatorsAlzheimer's diseaseMouse modelPhospho-tau accumulationAged mouse modelAlzheimer mouse modelImmune-mediated attackSAM treatmentMicroglial mediatorsSynaptic engulfmentSynaptic lossAD miceComplement component C1qSynapse lossGlutamate responseSynaptic densityDrug washoutSynaptic localizationTherapeutic benefitCognitive impairmentAllosteric modulatorsEmission tomographyNonhuman primatesComponent C1q
2020
Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy
Tang SJ, Fesharaki-Zadeh A, Takahashi H, Nies SH, Smith LM, Luo A, Chyung A, Chiasseu M, Strittmatter SM. Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy. Acta Neuropathologica Communications 2020, 8: 96. PMID: 32611392, PMCID: PMC7329553, DOI: 10.1186/s40478-020-00976-9.Peer-Reviewed Original ResearchConceptsRepetitive closed head injuriesMemory deficitsPhospho-tau accumulationChronic variable stressPersistent memory deficitsP301S transgenic miceClosed head injuryFyn inhibitionPassive avoidance learningFyn kinaseGlial activationPhospho-tauPresynaptic markersSynapse lossTau accumulationHead injurySynapse densityPhosphorylated tauTherapeutic benefitTransgenic miceBehavioral improvementTrauma modelTauopathiesSpatial memoryAvoidance learning
2019
In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease
Toyonaga T, Smith LM, Finnema SJ, Gallezot JD, Naganawa M, Bini J, Mulnix T, Cai Z, Ropchan J, Huang Y, Strittmatter SM, Carson RE. In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease. Journal Of Nuclear Medicine 2019, 60: 1780-1786. PMID: 31101744, PMCID: PMC6894376, DOI: 10.2967/jnumed.118.223867.Peer-Reviewed Original ResearchConceptsAPP/PS1 micePS1 miceAlzheimer's diseaseWT miceSynaptic densityC-UCBDrug washoutTreatment effectsPresenilin 1 (PS1) double transgenic miceHippocampal synaptic densityAPP/PS1Double transgenic miceEnd of treatmentWild-type miceAmyloid precursor proteinEarly Alzheimer's diseaseSignificant differencesSUVR-1New PET tracersMild cognitive impairmentAD miceSynaptic deficitsOral gavageAD treatmentHealthy subjectsAnti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice
Cox TO, Gunther EC, Brody AH, Chiasseu MT, Stoner A, Smith LM, Haas LT, Hammersley J, Rees G, Dosanjh B, Groves M, Gardener M, Dobson C, Vaughan T, Chessell I, Billinton A, Strittmatter SM. Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice. Annals Of Clinical And Translational Neurology 2019, 6: 554-574. PMID: 30911579, PMCID: PMC6414488, DOI: 10.1002/acn3.730.Peer-Reviewed Original ResearchConceptsAPP/PS1 transgenic micePS1 transgenic miceBrain antibodiesTransgenic miceDisease pathophysiologyDisease pathologyTransgenic Alzheimer's miceAlzheimer's disease pathologyAlzheimer's disease pathophysiologyHuman monoclonal antibodyPreclinical therapeutic efficacyHigh-affinity receptorAmyloid-beta oligomersLast doseTransgenic brainsPlaque pathologyAlzheimer's micePreclinical dataSynaptic damageAnti-PrPc antibodiesSynaptic densityIntraperitoneal dosingBrain biochemistryCentral synapsesTherapeutic efficacyPyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss
Lee S, Salazar SV, Cox TO, Strittmatter SM. Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss. Journal Of Neuroscience 2019, 39: 1910-1929. PMID: 30626696, PMCID: PMC6407289, DOI: 10.1523/jneurosci.2983-18.2018.Peer-Reviewed Original ResearchConceptsDendritic spine lossGenetic variationRhoA GTPaseSynapse lossSpine lossBiochemical basisGTPase-activating proteinsFocal adhesion kinasePyk2 functionPyk2 tyrosine kinasePostsynaptic sitesTyrosine kinase Pyk2Disease riskKinase-dependent mechanismOverexpression of Pyk2Dendritic spine densityAdhesion kinaseTransgenic mouse modelBiochemical isolationPyk2 kinaseAlzheimer's disease riskDendritic spine stabilityKinase Pyk2Late-onset Alzheimer's disease (LOAD) riskActin control
2018
Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss
Salazar SV, Cox TO, Lee S, Brody AH, Chyung AS, Haas LT, Strittmatter SM. Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss. Journal Of Neuroscience 2018, 39: 758-772. PMID: 30518596, PMCID: PMC6343652, DOI: 10.1523/jneurosci.1873-18.2018.Peer-Reviewed Original ResearchConceptsTransgenic AD model miceAD model miceAbsence of Pyk2Synaptic dysfunctionModel miceHippocampal slicesSynaptic transmissionAlzheimer's diseaseAmyloid-β plaque pathologyHippocampal Schaffer collateral pathwayDisease riskLearning/memory deficitsDeletion of Pyk2Suppression of LTPBasal synaptic transmissionLate-onset Alzheimer's diseaseImpairment of learningSchaffer collateral pathwayAD-related synaptic dysfunctionAlzheimer's disease riskLate-onset Alzheimer's disease (LOAD) riskOnset Alzheimer's diseaseAge-dependent lossMechanism of actionSynaptic LTD
2017
Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model
Smith LM, Zhu R, Strittmatter SM. Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model. Neuropharmacology 2017, 130: 54-61. PMID: 29191754, PMCID: PMC5743608, DOI: 10.1016/j.neuropharm.2017.11.042.Peer-Reviewed Original ResearchConceptsAlzheimer's modelDisease-modifying effectsDisease-modifying therapiesMouse Alzheimer’s modelsTherapy withdrawalAPPswe/Investigational agentsSynapse densityDrug washoutTransgenic modelAlzheimer's diseasePersistent benefitsPersistent improvementSaracatinibFyn inhibitorMemantineLoss of benefitDiseaseSpatial memoryMemory functionWashoutTherapySymptomsMiceWeeksChapter Thirteen Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5
Brody AH, Strittmatter SM. Chapter Thirteen Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5. Advances In Pharmacology 2017, 82: 293-323. PMID: 29413525, PMCID: PMC5835229, DOI: 10.1016/bs.apha.2017.09.007.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseNovel potential therapeutic targetDisease-modifying AD therapiesPotential therapeutic targetAmyloid-beta oligomersPrion proteinSynapse lossTau pathologySynaptic dysfunctionAD symptomsSynaptic damageAD pathophysiologyNeuronal dysfunctionSynaptic toxicityDisease progressionAD progressionAD therapyMemory dysfunctionTherapeutic targetCellular prion proteinBeta oligomersDysfunctionDiseaseGlobal health crisisMGluR5Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease
Salazar SV, Gallardo C, Kaufman AC, Herber CS, Haas LT, Robinson S, Manson JC, Lee MK, Strittmatter SM. Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease. Journal Of Neuroscience 2017, 37: 9207-9221. PMID: 28842420, PMCID: PMC5607466, DOI: 10.1523/jneurosci.0722-17.2017.Peer-Reviewed Original ResearchConceptsDisease onsetAlzheimer's diseaseFamilial Alzheimer's diseaseDisease pathophysiologyCellular prion proteinHippocampal synapse lossSoluble oligomeric amyloidTransgenic Alzheimer's diseaseTime of diagnosisDisease-modifying therapiesAlzheimer's disease pathophysiologyPotential therapeutic targetAD-related phenotypesMonths of ageRole of PrPSymptom onsetSynaptic deficitsPrion proteinSynapse lossCatecholaminergic neuronsPlaque densityBehavioral deficitsOligomeric amyloidMouse modelPresent symptoms
2013
Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease
Um JW, Strittmatter SM. Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion 2013, 7: 37-41. PMID: 22987042, PMCID: PMC3609048, DOI: 10.4161/pri.22212.Peer-Reviewed Original ResearchConceptsCellular prion proteinPrion proteinSignal transduction downstreamTransduction downstreamAlzheimer's diseaseFyn kinaseFunctional consequencesAβ oligomersAmyloid-β OligomersNeuronal surfaceHigh-affinity receptorOligomer complexesAD-related phenotypesCentral roleProteinAD pathogenesisRecent evidencePrevalent causeTherapeutic interventionsFynKinaseOligomersPhenotypeDiseaseDownstream
2012
Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons
Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature Neuroscience 2012, 15: 1227-1235. PMID: 22820466, PMCID: PMC3431439, DOI: 10.1038/nn.3178.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsBlotting, WesternCalcium SignalingCell LineDendritic SpinesElectroencephalographyEnzyme ActivationHumansMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicNeuronsPhosphorylationProtein BindingProto-Oncogene Proteins c-fynPrPC ProteinsRatsReceptors, N-Methyl-D-AspartateSeizuresSynapses
2010
Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse
Chung E, Ji Y, Sun Y, Kascsak RJ, Kascsak RB, Mehta PD, Strittmatter SM, Wisniewski T. Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse. BMC Neuroscience 2010, 11: 130. PMID: 20946660, PMCID: PMC2964735, DOI: 10.1186/1471-2202-11-130.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsAntibodies, MonoclonalBlotting, WesternCerebral CortexCognition DisordersEnzyme-Linked Immunosorbent AssayHippocampusHumansImage Processing, Computer-AssistedImmunohistochemistryMemory, Short-TermMiceMice, TransgenicPrPC ProteinsPsychomotor PerformanceSynapsesSynaptophysinConceptsAPP/PS1 Tg miceAPP/PS1 transgenic miceAPP/PS1 TgPS1 transgenic miceDisease model miceTransgenic miceCognitive deficitsTg miceAβ oligomersBehavioral testingVehicle solutionAlzheimer's disease model miceDentate gyrus molecular layerAPP/PS1 groupWild-type control groupConformational neurodegenerative disordersMonoclonal antibody infusionAD transgenic miceAmyloid plaque burdenAβ oligomer levelsDays/weekNovel therapeutic approachesMurine hippocampal slicesShort-term treatmentAnti-PrP antibodies
2009
An Unbiased Expression Screen for Synaptogenic Proteins Identifies the LRRTM Protein Family as Synaptic Organizers
Linhoff MW, Laurén J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig AM. An Unbiased Expression Screen for Synaptogenic Proteins Identifies the LRRTM Protein Family as Synaptic Organizers. Neuron 2009, 61: 734-749. PMID: 19285470, PMCID: PMC2746109, DOI: 10.1016/j.neuron.2009.01.017.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCells, CulturedCloning, MolecularCricetinaeCricetulusDisks Large Homolog 4 ProteinEmbryo, MammalianGene ExpressionGene Expression RegulationGene LibraryGenetic TestingGuanylate KinasesHippocampusHumansIntracellular Signaling Peptides and ProteinsLuminescent ProteinsMembrane PotentialsMembrane ProteinsMiceMice, KnockoutNeuronsPatch-Clamp TechniquesPDZ DomainsPresynaptic TerminalsRatsSynapsesTransfectionVesicular Glutamate Transport Protein 1ConceptsExpression screenSynaptogenic proteinsTrans-synaptic signalingDomain proteinsProtein familyTransmembrane proteinCDNA libraryMolecular basisSynaptogenic activityPresynaptic differentiationVesicular glutamate transporter VGLUT1Postsynaptic differentiationSynaptic organizersSynapse developmentPositive clonesCocultures of neuronsReported linkageLRRTMsCellular basisProteinGlutamate transporter VGLUT1LRRTM1Synaptic functionCurrent understandingAltered distributionCellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 2009, 457: 1128-1132. PMID: 19242475, PMCID: PMC2748841, DOI: 10.1038/nature07761.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAmyloidosisAnimalsChlorocebus aethiopsCOS CellsHippocampusHumansLong-Term PotentiationMiceMice, Inbred C57BLNeuronal PlasticityNeuronsPeptide FragmentsPrionsProtein BindingProtein MultimerizationReceptors, Cell SurfaceSynapsesConceptsCellular prion protein PrPCPrion protein PrPCSoluble amyloid-β peptide (Aβ) oligomersAlzheimer's diseaseCellular prion proteinDisease pathologyPlasma membrane glycoproteinsCell surface receptorsHigh affinity cell surface receptorsAlzheimer's disease pathologySoluble Aβ oligomersLipid raftsInfectious prion diseasesUnexpected linkMechanistic basisMembrane glycoproteinsPrion proteinAmyloid-β peptide (Aβ) oligomersSynaptic plasticityPrion diseasesTherapeutic potentialDiseaseAβ oligomersCentral roleDeleterious effects
2002
Localization of Nogo-A and Nogo-66 Receptor Proteins at Sites of Axon–Myelin and Synaptic Contact
Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA, Strittmatter SM. Localization of Nogo-A and Nogo-66 Receptor Proteins at Sites of Axon–Myelin and Synaptic Contact. Journal Of Neuroscience 2002, 22: 5505-5515. PMID: 12097502, PMCID: PMC6758202, DOI: 10.1523/jneurosci.22-13-05505.2002.Peer-Reviewed Original ResearchConceptsAdult CNSLimited axonal regenerationSpinal cord injuryNogo-66 receptorInteraction of NogoAxonal plasticityCord injurySynaptic contactsAxonal regenerationNgR proteinMyelinated fibersPostnatal neuronsLocalization of NogoMyelinated axonsAxonal growthOligodendrocyte surfacePhysiologic roleAxonsNogoProtein expressionNeuronsReceptorsInhibitory proteinInjuryCNS