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 ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsDisease Models, AnimalMiceMice, TransgenicNeuronsPrion ProteinsPrionsSynapsesTau ProteinsTranscriptomeConceptsSynapse 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 age
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 ResearchMeSH KeywordsAlzheimer DiseaseAnimalsComplement C1qDisease Models, AnimalMiceReceptor, Metabotropic Glutamate 5SynapsesConceptsPositron 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
Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury
Wang X, Zhou T, Maynard GD, Terse PS, Cafferty WB, Kocsis JD, Strittmatter SM. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain 2020, 143: 1697-1713. PMID: 32375169, PMCID: PMC7850069, DOI: 10.1093/brain/awaa116.Peer-Reviewed Original ResearchConceptsPrimate spinal cord injurySpinal cord injuryCord injuryFemale African green monkeysTreatment-related adverse eventsChronic neurological deficitsNogo receptor 1Left motor cortexRecovery of functionPreclinical rodent modelsSpinal cord injury animalsAfrican green monkeysRaphespinal fibersAdverse eventsCervical cordNeurological deficitsSurgical complicationsCNS traumaTreatment cessationCorticospinal axonsLumbar catheterInjury animalsNeural recoverySpontaneous feedingLateral hemisectionThe stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival
Schulz A, Sekine Y, Oyeyemi MJ, Abrams AJ, Basavaraju M, Han SM, Groth M, Morrison H, Strittmatter SM, Hammarlund M. The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival. Journal Of Cell Biology 2020, 219: e201807127. PMID: 31968056, PMCID: PMC7041677, DOI: 10.1083/jcb.201807127.Peer-Reviewed Original ResearchConceptsNeuronal stress resistanceStress resistanceNovel cellular responsesMouse neuronsVariety of stressesCaenorhabditis elegansC. elegansTranscriptional analysisSingle homologueEnvironmental stressFunctional characterizationCellular responsesCell deathNeuronal cell deathNeuronal glycogenGlycogen metabolismWidespread neuronal cell deathElegansSurvival of animalsTauopathy modelMaladaptive responsesKey roleHomologuesGlycogen levelsKnockdown
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 efficacySystematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance
Smith LM, Kostylev MA, Lee S, Strittmatter SM. Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance. Journal Of Biological Chemistry 2019, 294: 6042-6053. PMID: 30787106, PMCID: PMC6463724, DOI: 10.1074/jbc.ra118.006252.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAD brainLeukocyte immunoglobulin-like receptorsNogo receptor 1Human AD brainsImmunoglobulin-like receptorsB member 2Brains of individualsReceptor candidatesSoluble AβOsDisease relevanceCell surface expressionHippocampal neuronsMouse modelSynthetic AβAβO bindingMemory impairmentReceptor 1Cellular prion proteinNeuronal synapsesNgR1Molecular pathologyAβAβ speciesMember 2
2018
Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer’s Disease: APP/PS1, 3xTgAD, and Tg2576
Kent BA, Strittmatter SM, Nygaard H. Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer’s Disease: APP/PS1, 3xTgAD, and Tg2576. Journal Of Alzheimer's Disease 2018, 64: 1325-1336. PMID: 29991134, PMCID: PMC6176720, DOI: 10.3233/jad-180260.Peer-Reviewed Original Research
2017
Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network
Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM, For the Alzheimer’s Disease Neuroimaging Initiative. Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathologica 2017, 133: 785-807. PMID: 28070672, PMCID: PMC5391267, DOI: 10.1007/s00401-017-1668-z.Peer-Reviewed Original ResearchConceptsAPP/PS1 micePS1 micePGRN deficiencyAlzheimer's diseaseAD risk variantsCerebrospinal fluid Aβ levelsLoss of progranulinMicroglial Aβ phagocytosisCSF tau levelsFrontotemporal lobar degenerationRisk variantsAPPswe/Aβ phagocytosisNeuronal injuryAβ levelsAβ pathologyCerebral amyloidosisAxonal dystrophyTau pathologyTau levelsComplement depositionPGRN levelsAD pathophysiologyAmyloid imagingProgranulin deficiency
2016
Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury
Wang X, Sekine Y, Byrne AB, Cafferty WB, Hammarlund M, Strittmatter SM. Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury. ENeuro 2016, 3: eneuro.0270-16.2016. PMID: 28032120, PMCID: PMC5187389, DOI: 10.1523/eneuro.0270-16.2016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsBenzimidazolesCells, CulturedCerebral CortexDisease Models, AnimalFemaleIsoenzymesMaleMice, 129 StrainMice, Inbred C57BLMice, TransgenicMotor ActivityNerve RegenerationOptic Nerve InjuriesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsRecovery of FunctionSpinal Cord InjuriesThoracic VertebraeConceptsOptic nerve crush injuryNerve crush injuryThoracic spinal cordAxonal regenerationSpinal cordDorsal hemisectionCrush injuryFunctional recoveryPARP inhibitorsMotor function recoveryRecovery of functionPoly (ADP-ribose) polymeraseClinical PARP inhibitorsNeurological recoveryShort hairpin RNACNS traumaCNS injuryFunction recoveryAxonal regrowthSystemic administrationPharmacodynamic actionAxon regenerationTraumatic damageTherapeutic efficacyNeurological traumaEarly Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease.
Heiss JK, Barrett J, Yu Z, Haas LT, Kostylev MA, Strittmatter SM. Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease. Cerebral Cortex 2016, 27: 3660-3674. PMID: 27365298, PMCID: PMC6059166, DOI: 10.1093/cercor/bhw188.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAlzheimer DiseaseAmyloid beta-Protein PrecursorAnalysis of VarianceAnimalsCerebral CortexDendritic SpinesDisease Models, AnimalGene Expression ProfilingGreen Fluorescent ProteinsHippocampusHumansImaging, Three-DimensionalImmunoprecipitationMiceMice, Inbred C57BLMice, TransgenicMutationNeuroimagingPlaque, AmyloidPresenilin-1Prion ProteinsProto-Oncogene Proteins c-fosSensory DeprivationTime FactorsVibrissaeConceptsAPP/PS1 miceDendritic spine turnoverSpine turnoverAlzheimer's diseasePS1 miceAged APP/PS1 miceYoung APP/PS1 miceAPP/PS1 mouse brainSoluble Aβ oligomersLipid-metabolizing genesAPPswe/Synaptic lossCerebral cortexSynapse densityAβ plaquesSynaptic dysregulationLack responsivenessMouse modelDendritic spinesPersistent spinesSynapse turnoverPlaque formationMouse brainYounger ageCellular prion proteinOligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease*
Haas LT, Strittmatter SM. Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease*. Journal Of Biological Chemistry 2016, 291: 17112-17121. PMID: 27325698, PMCID: PMC5016115, DOI: 10.1074/jbc.m116.720664.Peer-Reviewed Original ResearchConceptsProtein tyrosine kinase 2Calmodulin-dependent protein kinase IICalcium/calmodulin-dependent protein kinase IICellular prion proteinProtein kinase IIBrain slicesSignaling cascadesAlzheimer's diseaseKinase IIPhysiological signalingKinase 2Mutant transgeneMetabotropic glutamate receptor 5Loss of synapsesPrion proteinGlutamate receptor 5Receptor complexWild-type slicesProtein mediatorsAmyloid-β OligomersGlutamate activationChronic expressionDementia symptomsReceptor 5Acute exposure
2015
Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice
Fink KL, Strittmatter SM, Cafferty WB. Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice. Journal Of Neuroscience 2015, 35: 15403-15418. PMID: 26586827, PMCID: PMC4649010, DOI: 10.1523/jneurosci.3165-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAmidinesAnalysis of VarianceAnimalsAxonsBiotinCrystallinsDextransDisease Models, AnimalFunctional LateralityGene Expression RegulationGlial Fibrillary Acidic ProteinGPI-Linked ProteinsLuminescent ProteinsMiceMice, Inbred C57BLMice, TransgenicMu-CrystallinsMyelin ProteinsNerve RegenerationNogo Receptor 1Pyramidal TractsReceptors, Cell SurfaceRecovery of FunctionSpinal Cord InjuriesConceptsCorticospinal tractCST axonsTransgenic miceMotor tractsDextran amineFunctional deficitsSpinal cordAxon regenerationSpinal Cord Injury StudySpontaneous axon regenerationSpinal cord traumaNogo receptor 1Permanent functional deficitsPersistent functional deficitsBilateral pyramidotomyDorsal hemisectionMidthoracic cordCord traumaMotor pathwaysAdult CNSCST regenerationInjury studiesLesion siteRegenerating fibersNeural repairGene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury
Zou Y, Stagi M, Wang X, Yigitkanli K, Siegel CS, Nakatsu F, Cafferty WB, Strittmatter SM. Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury. Journal Of Neuroscience 2015, 35: 10429-10439. PMID: 26203138, PMCID: PMC4510284, DOI: 10.1523/jneurosci.1718-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsDisease Models, AnimalGene Knockdown TechniquesImmunohistochemistryInositol Polyphosphate 5-PhosphatasesMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationPhosphoric Monoester HydrolasesRecovery of FunctionReverse Transcriptase Polymerase Chain ReactionSpinal Cord InjuriesConceptsSpinal cord injuryCord injuryEndogenous suppressorAxon regenerationNonoverlapping substrate specificityGenome-wide scaleHigh-throughput functional screensFunctional recoveryAxonal regenerationCNS axon repairSpinal cord injury researchDorsal hemisection injuryMammalian genesPI3K/AKT/mTOR pathwayCNS axon growthAKT/mTOR pathwayLipid phosphataseCorticospinal tract axonsCNS axon regenerationAdult mammalian CNSFunctional screenSubstrate specificityNovel suppressorShRNA resultsINPP5FPrion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models*
Kostylev MA, Kaufman AC, Nygaard HB, Patel P, Haas LT, Gunther EC, Vortmeyer A, Strittmatter SM. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models*. Journal Of Biological Chemistry 2015, 290: 17415-17438. PMID: 26018073, PMCID: PMC4498078, DOI: 10.1074/jbc.m115.643577.Peer-Reviewed Original ResearchAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAnimalsBehavior, AnimalDisease Models, AnimalFemaleHumansMaleMemory DisordersMiceMice, Inbred C57BLMice, Mutant StrainsMice, TransgenicMiddle AgedMolecular WeightPrefrontal CortexPresenilin-1PrionsProtein Structure, QuaternaryPrPC ProteinsRecombinant ProteinsFyn inhibition rescues established memory and synapse loss in Alzheimer mice
Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Annals Of Neurology 2015, 77: 953-971. PMID: 25707991, PMCID: PMC4447598, DOI: 10.1002/ana.24394.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseTransgenic miceGlu receptorsAPP/PS1 transgenic miceAPP/PS1 miceMemory deficitsEffective disease-modifying agentsAD mouse modelPS1 transgenic miceAD transgenic miceDisease-modifying agentsTau transgenic miceWeeks of treatmentPrecursor protein metabolismSpatial memory deficitsNovel object recognitionMorris water mazeBrain slice assaysAZD0530 treatmentMicroglial activationPS1 miceVehicle treatmentSynapse lossAlzheimer's miceAD pathologyIntravitreal Delivery of Human NgR-Fc Decoy Protein Regenerates Axons After Optic Nerve Crush and Protects Ganglion Cells in Glaucoma ModelsNgR-Fc Rescues Ganglion Cells in Glaucoma
Wang X, Lin J, Arzeno A, Choi JY, Boccio J, Frieden E, Bhargava A, Maynard G, Tsai JC, Strittmatter SM. Intravitreal Delivery of Human NgR-Fc Decoy Protein Regenerates Axons After Optic Nerve Crush and Protects Ganglion Cells in Glaucoma ModelsNgR-Fc Rescues Ganglion Cells in Glaucoma. Investigative Ophthalmology & Visual Science 2015, 56: 1357-1366. PMID: 25655801, PMCID: PMC4338631, DOI: 10.1167/iovs.14-15472.Peer-Reviewed Original ResearchConceptsOptic nerve crushFluro-GoldNerve crushAxonal regenerationGanglion cellsOptic nerve crush injuryRetinal ganglion cell degenerationRGC axonal regenerationNerve crush injuryDisease-modifying therapiesGanglion cell degenerationDecoy proteinMicrobead modelVitreal spaceIntravitreal treatmentRGC densityAxonal sproutingCrush injuryGlaucoma modelNeuroprotective effectsAnterior chamberControl ratsVision lossAnterograde labelingBolus administration
2014
Human NgR-Fc Decoy Protein via Lumbar Intrathecal Bolus Administration Enhances Recovery from Rat Spinal Cord Contusion
Wang X, Yigitkanli K, Kim CY, Sekine-Konno T, Wirak D, Frieden E, Bhargava A, Maynard G, Cafferty WB, Strittmatter SM. Human NgR-Fc Decoy Protein via Lumbar Intrathecal Bolus Administration Enhances Recovery from Rat Spinal Cord Contusion. Journal Of Neurotrauma 2014, 31: 1955-1966. PMID: 24964223, PMCID: PMC4245872, DOI: 10.1089/neu.2014.3355.Peer-Reviewed Original ResearchConceptsSpinal cord injuryTraumatic spinal cord injurySpinal cord contusionNeurological recoveryCord contusionRat spinal cord contusionSpinal contusion injuryLumbar intrathecal spaceLumbar spinal cordContinuous intracerebroventricular infusionRodent SCI modelsPercentage of ratsRaphespinal axonsContusion injuryAdministration regimenSCI modelContinuous infusionCord injuryIntracerebroventricular infusionIntrathecal spaceSpinal cordPreclinical modelsEffective treatmentWalking tasksClinical testingTherapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)*
Haas LT, Kostylev MA, Strittmatter SM. Therapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)*. Journal Of Biological Chemistry 2014, 289: 28460-28477. PMID: 25148681, PMCID: PMC4192497, DOI: 10.1074/jbc.m114.584342.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsAntibodiesBinding SitesBiological AssayBrain ChemistryCell MembraneDisease Models, AnimalGene Expression RegulationHEK293 CellsHumansLigandsMiceMice, TransgenicPeptide MappingProtein BindingProtein Structure, TertiaryPrPC ProteinsReceptor, Metabotropic Glutamate 5Recombinant ProteinsSignal TransductionSmall Molecule LibrariesConceptsMetabotropic glutamate receptor 5Glutamate receptor 5Receptor 5Endogenous ligandMouse brainAD transgenic model miceCellular prion proteinAmino acids 91Transgenic model miceSoluble amyloid β (Aβ) oligomersAlzheimer's disease pathophysiologySilent allosteric modulatorsAgonists/antagonistsExtracellular AβOsMGluR5 activitySynthetic AβOsPrion proteinAmyloid-β OligomersModel miceCell membrane preparationsMGluR5Neurotoxic signalsBrain homogenatesAlzheimer's diseaseDisease pathophysiologyDiffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery
Kelley BJ, Harel NY, Kim CY, Papademetris X, Coman D, Wang X, Hasan O, Kaufman A, Globinsky R, Staib LH, Cafferty WB, Hyder F, Strittmatter SM. Diffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery. Journal Of Neurotrauma 2014, 31: 1362-1373. PMID: 24779685, PMCID: PMC4120934, DOI: 10.1089/neu.2013.3238.Peer-Reviewed Original ResearchConceptsSpinal cord injuryDiffusion tensor imagingCord injuryAxonal integrityLocomotor functionExperimental spinal cord injuryTraumatic spinal cord injuryFemale Sprague-Dawley ratsTensor imagingFractional anisotropyFunctional recovery assessmentSpinal cord contusionLimited functional recoveryLong-term disabilityQuantitative diffusion tensor imagingRodent SCI modelsSprague-Dawley ratsSpinal cord morphologyWhite matter pathologyCaudal spinal cordWhite matter integrityInjury epicenterMidthoracic laminectomyCord contusionPrimary outcome