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
PET imaging of mGluR5 in Alzheimer’s disease
Mecca AP, McDonald JW, Michalak HR, Godek TA, Harris JE, Pugh EA, Kemp EC, Chen MK, Salardini A, Nabulsi NB, Lim K, Huang Y, Carson RE, Strittmatter SM, van Dyck CH. PET imaging of mGluR5 in Alzheimer’s disease. Alzheimer's Research & Therapy 2020, 12: 15. PMID: 31954399, PMCID: PMC6969979, DOI: 10.1186/s13195-020-0582-0.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAlzheimer DiseaseBrainCognitive DysfunctionFemaleHumansMaleMiddle AgedPositron-Emission TomographyRadiopharmaceuticalsReceptor, Metabotropic Glutamate 5ConceptsEarly Alzheimer's diseaseAlzheimer's diseaseMild cognitive impairmentBrain amyloidHippocampus of ADPositron emission tomography radioligandSubtype 5 receptorsMild AD dementiaGray matter atrophyAssociation cortical regionsAmnestic mild cognitive impairmentImportant therapeutic targetCerebellum reference regionDynamic PET scansHippocampal mGluR5MethodsSixteen individualsMGluR5 bindingSynaptotoxic actionAD dementiaAD pathogenesisMatter atrophyInitial administrationAD groupSynaptic transmissionEntorhinal cortex
2018
Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer’s Amyloid-β Oligomers
Kostylev MA, Tuttle MD, Lee S, Klein LE, Takahashi H, Cox TO, Gunther EC, Zilm KW, Strittmatter SM. Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer’s Amyloid-β Oligomers. Molecular Cell 2018, 72: 426-443.e12. PMID: 30401430, PMCID: PMC6226277, DOI: 10.1016/j.molcel.2018.10.009.Peer-Reviewed Original ResearchConceptsAmino-terminal GlyCellular prion proteinProtein phase separationAmyloid-β OligomersPlasma membraneMembraneless organellesAla residuesRecombinant PrPPrion proteinCell surfaceConformation shiftConformational transitionHelical conformationAβ speciesPrPSupSpongiform degenerationEndogenous AβOsOrganellesPrPCSuch domainsSpeciesDomainProteinAβOs
2017
Chapter 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 ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsHumansPrion ProteinsReceptor, Metabotropic Glutamate 5Signal TransductionSynapsesConceptsAlzheimer'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 crisisMGluR5Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes
Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, Degnan AP, Balakrishnan A, Macor JE, Albright CF, Strittmatter SM. Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes. Cell Reports 2017, 20: 76-88. PMID: 28683325, PMCID: PMC5547898, DOI: 10.1016/j.celrep.2017.06.023.Peer-Reviewed Original ResearchConceptsAD transgenic mouse modelDisease pathologyMetabotropic glutamate receptor 5Allosteric modulationGlutamate receptor 5Alzheimer's disease pathologyTransgenic mouse brainSilent allosteric modulatorsTransgenic mouse modelBroad therapeutic windowMouse phenotypeAD interventionSynaptic depletionBrain slicesGlutamate signalingMouse modelTherapeutic windowAD phenotypeReceptor 5Mouse brainAllosteric modulatorsMemory deficitsCellular prion proteinPathological roleMGluR5
2016
Oligomers 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 ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsDisease Models, AnimalFemaleGlutamic AcidMaleMiceMice, TransgenicPeptide FragmentsProtein Aggregation, PathologicalPrPC ProteinsReceptor, Metabotropic Glutamate 5ConceptsProtein 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
Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease
Haas LT, Salazar SV, Kostylev MA, Um JW, Kaufman AC, Strittmatter SM. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease. Brain 2015, 139: 526-546. PMID: 26667279, PMCID: PMC4840505, DOI: 10.1093/brain/awv356.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAnimalsFrontal LobeHEK293 CellsHumansIntracellular FluidMiceMice, Inbred C57BLMice, KnockoutOrgan Culture TechniquesPrion ProteinsPrionsProtein BindingReceptor, Metabotropic Glutamate 5Signal TransductionConceptsCellular prion proteinDisease-related phenotypesPrion proteinMetabotropic glutamate receptor 5Glutamate receptor 5Protein tyrosine kinase 2 betaCalmodulin-dependent protein kinase IICalcium/calmodulin-dependent protein kinase IIProtein kinase IIReceptor 5Protein associatesGenetic interactionsObligate complexesGenetic couplingDisease pathogenesisDisease pathologyKinase IIIntracellular proteinsAlzheimer's disease-related phenotypesSingle heterozygotesProteinBiochemical evidenceProtein mediatorsDisease-modifying interventionsTransgenic model mice
2014
Therapeutic 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 pathophysiology
2013
Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein
Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein. Neuron 2013, 79: 887-902. PMID: 24012003, PMCID: PMC3768018, DOI: 10.1016/j.neuron.2013.06.036.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCalciumCells, CulturedElongation Factor 2 KinaseHEK293 CellsHumansMiceNeuronsOocytesPhosphorylationPost-Synaptic DensityProto-Oncogene Proteins c-fynPrPC ProteinsReceptor, Metabotropic Glutamate 5Receptors, Metabotropic GlutamateSignal TransductionXenopusConceptsDisease pathophysiologyHuman AD brain extractsCellular prion proteinMetabotropic glutamate receptor 5Postsynaptic densityDendritic spine lossAD brain extractsMetabotropic glutamate receptorsGlutamate receptor 5Alzheimer's disease pathophysiologyExtracellular AβOsMGluR5 antagonismPrion proteinSpine lossSynapse densityGlutamate receptorsIntracellular calciumMGluR5Receptor 5Neuronal functionAβOsBrain extractsAβ oligomersFyn kinasePSD proteins