Featured Publications
Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo
Damisah EC, Hill RA, Rai A, Chen F, Rothlin CV, Ghosh S, Grutzendler J. Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo. Science Advances 2020, 6: eaba3239. PMID: 32637606, PMCID: PMC7319765, DOI: 10.1126/sciadv.aba3239.Peer-Reviewed Original ResearchConceptsCorpse removalPrecise spatiotemporal resolutionApoptotic cell removalReceptor tyrosine kinasesGlial cellsOrchestrated rolesTyrosine kinaseApoptotic bodiesCell deathSpecialized roleCoordinated interactionPhagocytic interactionSingle cellsBrain homeostasisCellsCell removalIntravital optical imagingSpatiotemporal resolutionRole of phagocytesSynchronized fashionKinaseMarked delayRoleHomeostasisAstrocytesMicroglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello C, Yuan P, Grutzendler J. Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging. Biological Psychiatry 2017, 83: 377-387. PMID: 29169609, PMCID: PMC5767550, DOI: 10.1016/j.biopsych.2017.10.007.Peer-Reviewed Original ResearchConceptsAlzheimer's diseasePlaque compactionAmyloid depositsInvolvement of microgliaPlaque-associated microgliaLate-onset Alzheimer's diseaseMyeloid cells 2Onset Alzheimer's diseaseMicroglia receptorMicroglia polarizationAD neuropathologyAxonal pathologyNeuroprotective functionDisease progressionOptical imaging studiesCurrent evidenceAD riskMicrogliaTherapeutic targetingAdjacent axonsImaging studiesCells 2DiseasePrecise mechanismRecent genetic studiesTREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 2016, 90: 724-739. PMID: 27196974, PMCID: PMC4898967, DOI: 10.1016/j.neuron.2016.05.003.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAxonal dystrophyAmyloid depositsAD-like miceHuman AD tissueLate-onset Alzheimer's diseaseNovel therapeutic strategiesTREM2 deficiencyTau hyperphosphorylationAD tissueMicroglia processesPharmacological modulationCompact plaquesTherapeutic strategiesHigh-resolution confocalTREM2 mutationsTREM2Barrier functionMiceGreater surface exposureAmyloid fibrilsHaplodeficiencyPlaquesDiseaseDystrophyMicroglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nature Communications 2015, 6: 6176. PMID: 25630253, PMCID: PMC4311408, DOI: 10.1038/ncomms7176.Peer-Reviewed Original ResearchAngiophagy Prevents Early Embolus Washout But Recanalizes Microvessels Through Embolus Extravasation
Grutzendler J, Murikinati S, Hiner B, Ji L, Lam CK, Yoo T, Gupta S, Hafler BP, Adelman RA, Yuan P, Rodriguez G. Angiophagy Prevents Early Embolus Washout But Recanalizes Microvessels Through Embolus Extravasation. Science Translational Medicine 2014, 6: 226ra31. PMID: 24598589, DOI: 10.1126/scitranslmed.3006585.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCerebrovascular CirculationCoronary CirculationEmbolismFibrinFibrinolysisFundus OculiGreen Fluorescent ProteinsHemodynamicsHumansKidney TubulesLungMacrophagesMiceMice, TransgenicMicrocirculationMicrogliaMicroscopy, Electron, TransmissionMicrovesselsMonocytesPhagocytosisRetinaRetinal VesselsThrombosisConceptsBlood flow reestablishmentHours of occlusionVascular occlusive disordersDifferent therapeutic strategiesEmbolic occlusionOcclusive disordersVessel recanalizationAlveolar spaceTherapeutic strategiesTherapeutic targetHemodynamic pressureFibrinolytic systemPerivascular spacesEmboliRenal tubulesBlood clotsMicrovascular wallMost human organsOcclusionLungExtravasationKidneyEndotheliumMicrovasculatureWashoutLabel-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy
Schain AJ, Hill RA, Grutzendler J. Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy. Nature Medicine 2014, 20: 443-449. PMID: 24681598, PMCID: PMC3981936, DOI: 10.1038/nm.3495.Peer-Reviewed Original ResearchAngiophagy
Grutzendler J. Angiophagy. Stroke 2013, 44: s84-s86. PMID: 23709741, DOI: 10.1161/strokeaha.112.678730.Peer-Reviewed Original ResearchEmbolus extravasation is an alternative mechanism for cerebral microvascular recanalization
Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature 2010, 465: 478-482. PMID: 20505729, PMCID: PMC2879083, DOI: 10.1038/nature09001.Peer-Reviewed Original ResearchConceptsAge-related cognitive disordersBlood vesselsPossible therapeutic targetAged miceBlood flowTherapeutic targetCognitive disordersMice showBlood clotsEndothelial cellsUnderlying endotheliumMicroemboliExtravasationFibrinolysisVesselsRecanalizationEmboliPatientsStrokeEndotheliumMiceBloodBrainWeeksClotsRegional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes
Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. Neuron 2015, 87: 95-110. PMID: 26119027, PMCID: PMC4487786, DOI: 10.1016/j.neuron.2015.06.001.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsCerebral blood flowBlood flowCapillary pericytesArteriolar smooth muscle cellsBlood flow regulationRegional blood flowNormal brain functionSmooth muscle actinSmooth muscle cell contractilityMuscle cell contractilityPericyte constrictionIschemic brainBrain ischemiaMicrovascular occlusionNeurovascular couplingMicrovascular diametersWhisker stimulationMuscle actinMuscle cellsBrain functionMajor causePathological conditionsPericytesVascular tree
2021
Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
Zhou HJ, Qin L, Jiang Q, Murray KN, Zhang H, Li B, Lin Q, Graham M, Liu X, Grutzendler J, Min W. Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model. Nature Communications 2021, 12: 504. PMID: 33495460, PMCID: PMC7835246, DOI: 10.1038/s41467-020-20774-0.Peer-Reviewed Original ResearchConceptsCerebral cavernous malformationsCCM lesionsSmooth muscle actin-positive pericytesEndothelial cell lossRegions of brainCCM pathogenesisPost-capillary venulesCerebral hemorrhagePharmacological blockadeVascular abnormalitiesEC-specific deletionCavernous malformationsMouse modelCell lossMicrovascular bedGenetic deletionLesion formationLesionsVascular dynamicsBarrier functionMicrovascular structureTwo-photon microscopyTie2PathogenesisMice
2020
TREM2: Modulator of Lipid Metabolism in Microglia
Damisah EC, Rai A, Grutzendler J. TREM2: Modulator of Lipid Metabolism in Microglia. Neuron 2020, 105: 759-761. PMID: 32135085, DOI: 10.1016/j.neuron.2020.02.008.Peer-Reviewed Original ResearchEmerging technologies to study glial cells
Hirbec H, Déglon N, Foo LC, Goshen I, Grutzendler J, Hangen E, Kreisel T, Linck N, Muffat J, Regio S, Rion S, Escartin C. Emerging technologies to study glial cells. Glia 2020, 68: 1692-1728. PMID: 31958188, DOI: 10.1002/glia.23780.Peer-Reviewed Original ResearchConceptsCell typesChallenging biological questionsGlial cellsSpecific cell typesDifferent glial cell typesGlial cell typesBiological questionsPhysiological functionsPrecursor cellsTight interactionOligodendrocyte precursor cellsCellsExperimental approachRelative contributionBrain functionFull understandingSpecific brain functionsRoleFunctionInteractionDevelopmentTranslation
2019
Cellular Control of Brain Capillary Blood Flow: In Vivo Imaging Veritas
Grutzendler J, Nedergaard M. Cellular Control of Brain Capillary Blood Flow: In Vivo Imaging Veritas. Trends In Neurosciences 2019, 42: 528-536. PMID: 31255380, PMCID: PMC7386067, DOI: 10.1016/j.tins.2019.05.009.Peer-Reviewed Original ResearchConceptsCapillary blood flowBlood flowBrain capillary blood flowRegional cerebral blood flowCerebral blood flowRed blood cell deformabilityBlood cell deformabilityMicrovascular perfusionNeurovascular couplingMicrovascular flowBrain metabolitesMural cellsLevel-dependent changesNeural activationVessel diameterMicrovascular treeNeural activityCell deformabilityCell controlDirect visualizationMethodological standardsVasomotilityPerfusionControlUncovering the biology of myelin with optical imaging of the live brain
Hill RA, Grutzendler J. Uncovering the biology of myelin with optical imaging of the live brain. Glia 2019, 67: 2008-2019. PMID: 31033062, PMCID: PMC6744352, DOI: 10.1002/glia.23635.Peer-Reviewed Original Research
2017
Oxalate-curcumin–based probe for micro- and macroimaging of reactive oxygen species in Alzheimer’s disease
Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C. Oxalate-curcumin–based probe for micro- and macroimaging of reactive oxygen species in Alzheimer’s disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 12384-12389. PMID: 29109280, PMCID: PMC5703278, DOI: 10.1073/pnas.1706248114.Peer-Reviewed Original ResearchConceptsCerebral amyloid angiopathyAD brainAlzheimer's diseaseTwo-photon imagingNIRF imagingAmyloid-beta plaquesROS levelsIrreversible neurodegenerative disorderAD pathological conditionsAge-related increaseReactive oxygen species levelsAmyloid angiopathyBeta plaquesOxygen species levelsDrug treatmentHealthy brainNeurodegenerative disordersDiseaseOxidative stressHigh ROS levelsPathological conditionsReactive oxygen speciesBrainFluorescence imaging probeOxygen species
2016
“Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop
Bosetti F, Galis Z, Bynoe M, Charette M, Cipolla M, del Zoppo G, Gould D, Hatsukami T, Jones T, Koenig J, Lutty G, Maric‐Bilkan C, Stevens T, Tolunay H, Koroshetz W, Participants T, Agalliu D, Antonetti D, Boehm M, Brooks C, Caron K, Chilian W, Daemen M, D'Amato R, Davis T, Ergul A, Faber J, Gomez A, Grayson P, Grumbach I, Grutzendler J, Gu C, Gutterman D, Hallenbeck J, Herman I, Humphrey J, Iadecola C, Inscho E, Kleinfeld D, Lo E, Lopez J, Macknik S, Malik A, Mayadas T, McGavern D, Meininger G, Miller V, Nedergaard M, Nelson M, Peirce‐Cottler S, Ramadan I, Rosenberg G, Schiffrin E, Searson P, Stachenfeld N, Stan R, Suarez Y, Ubogu E, Vexler Z, Weyand C, Zlokovic B. “Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop. Journal Of The American Heart Association 2016, 5: e004389. PMID: 27815267, PMCID: PMC5210346, DOI: 10.1161/jaha.116.004389.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsTREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. Journal Of Experimental Medicine 2016, 213: 667-675. PMID: 27091843, PMCID: PMC4854736, DOI: 10.1084/jem.20151948.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseTREM2 deficiencyAβ accumulationNeuritic damageAβ plaquesMyeloid cellsAbsence of TREM2Impact of TREM2Rare TREM2 variantsAmyloid β accumulationBrain-resident microgliaMyeloid cells 2Peripheral blood monocytesEarly time pointsMicroglial clusteringMicroglial receptorΒ accumulationAβ depositsNeuronal degenerationTREM2 variantsAmyloid plaquesMurine modelBlood monocytesMatter of debateMicrogliaIncreased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging
Han L, Kong DK, Zheng MQ, Murikinati S, Ma C, Yuan P, Li L, Tian D, Cai Q, Ye C, Holden D, Park JH, Gao X, Thomas JL, Grutzendler J, Carson RE, Huang Y, Piepmeier JM, Zhou J. Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging. ACS Nano 2016, 10: 4209-4218. PMID: 26967254, PMCID: PMC5257033, DOI: 10.1021/acsnano.5b07573.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBiological TransportBlood-Brain BarrierBrain NeoplasmsCell Line, TumorDecanoic AcidsDrug Delivery SystemsEthanolaminesFemaleGenetic TherapyHeterograftsHumansMatrix Metalloproteinase 2MiceMice, Inbred C57BLNanoparticlesOptical ImagingPaclitaxelPermeabilityPolymersPurinesPyrazolesScorpion VenomsTranscytosisTumor MicroenvironmentConceptsBlood-brain barrierLow delivery efficiencyTransport of nanoparticlesCancer gene therapyNanoparticle deliveryMore nanoparticlesBrain tumorsNanoparticlesDelivery efficiencyGene therapySystemic deliveryNPsBrain malignanciesBBB modulatorsPharmacological agentsBrain cancerBrain regionsTumorsDeliveryBrainImproved treatmentInadequate amountsPositive feedback loopChemotherapyMalignancyAttenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity
Yuan P, Grutzendler J. Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity. Journal Of Neuroscience 2016, 36: 632-641. PMID: 26758850, PMCID: PMC4710779, DOI: 10.1523/jneurosci.2531-15.2016.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsCalcium-Binding ProteinsClozapineDesigner DrugsDisease Models, AnimalHumansInsulysinLysosome-Associated Membrane GlycoproteinsMaleMiceMice, TransgenicMicrofilament ProteinsNerve Tissue ProteinsNeurotoxicity SyndromesPresenilin-1Proto-Oncogene Proteins c-fosStyrenesTransduction, GeneticConceptsAmyloid plaquesAlzheimer's diseaseNeuronal activityAmyloid depositionDisease miceNeural activityAD-like mouse modelNeural activity reductionΒ-amyloid depositionAlzheimer's disease miceNovel therapeutic approachesPotential therapeutic strategyViral-mediated deliveryChemogenetic modulationSynaptic lossAβ depositionSynaptic pathologyNeural hyperactivityAmyloid pathologyAxonal dystrophyDendritic fieldsChronic attenuationDesigner receptorsTherapeutic approachesMouse model
2015
Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli
Housley WJ, Fernandez SD, Vera K, Murikinati SR, Grutzendler J, Cuerdon N, Glick L, De Jager PL, Mitrovic M, Cotsapas C, Hafler DA. Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Science Translational Medicine 2015, 7: 291ra93. PMID: 26062845, PMCID: PMC4574294, DOI: 10.1126/scitranslmed.aaa9223.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAllelesAutoimmunityCase-Control StudiesCD4-Positive T-LymphocytesCell NucleusCytokinesFemaleGenetic Predisposition to DiseaseHumansInflammationMaleMiddle AgedMultiple SclerosisNF-kappa BPolymorphism, Single NucleotideProtein TransportReceptors, Tumor Necrosis Factor, Type IRisk FactorsSex CharacteristicsSignal TransductionTime FactorsTumor Necrosis Factor-alphaConceptsB-cell leukemia 3Multiple sclerosisNegative regulatorInflammatory stimuliGenetic variantsWide association studyDisease susceptibility variantsNaïve CD4 T cellsRapid genetic screeningCD4 T cellsActivation of p65Transcription factor nuclear factor κBExpression of NFκBNuclear factor κBApoptosis 1Cellular inhibitorGG risk genotypeDegradation of inhibitorCentral regulatorAssociation studiesCytokine blockadeUlcerative colitisAutoimmune diseasesTumor necrosisSusceptibility variants