Featured Publications
PLD3 affects axonal spheroids and network defects in Alzheimer’s disease
Yuan P, Zhang M, Tong L, Morse T, McDougal R, Ding H, Chan D, Cai Y, Grutzendler J. PLD3 affects axonal spheroids and network defects in Alzheimer’s disease. Nature 2022, 612: 328-337. PMID: 36450991, PMCID: PMC9729106, DOI: 10.1038/s41586-022-05491-6.Peer-Reviewed Original ResearchConceptsAxonal spheroidsAlzheimer's diseaseConduction blockadeNeural circuit abnormalitiesNeural network dysfunctionAmyloid removalCircuit abnormalitiesAge-dependent accumulationNetwork dysfunctionEndolysosomal vesiclesMouse modelNeuronal overexpressionCognitive declineAxonal connectivityDiseasePrecise mechanismBlockadePLD3Neural network functionSpheroid growthSevere disruptionCurrent sinkVoltage imagingSize-dependent mannerDysfunctionTargeted two-photon chemical apoptotic ablation of defined cell types in vivo
Hill RA, Damisah EC, Chen F, Kwan AC, Grutzendler J. Targeted two-photon chemical apoptotic ablation of defined cell types in vivo. Nature Communications 2017, 8: 15837. PMID: 28621306, PMCID: PMC5501159, DOI: 10.1038/ncomms15837.Peer-Reviewed Original ResearchConceptsCell deathNucleic acid-binding dyeVivo functional consequencesCell type differencesPattern of apoptosisDose-dependent apoptosisComplex organismsMitochondrial fissionFluorescent proteinUnderstanding of mechanismsCell typesCell clearanceFunctional consequencesIndividual cellsDiverse organsDistinct populationsApoptosisMouse brainZebrafishMajor bottleneckNeural plasticityOrganismsSpeciesProteinApoptoticTREM2 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 fibrilsHaplodeficiencyPlaquesDiseaseDystrophyA fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging
Damisah EC, Hill RA, Tong L, Murray KN, Grutzendler J. A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging. Nature Neuroscience 2017, 20: 1023-1032. PMID: 28504673, PMCID: PMC5550770, DOI: 10.1038/nn.4564.Peer-Reviewed Original ResearchLifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain
Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nature Neuroscience 2018, 21: 683-695. PMID: 29556031, PMCID: PMC5920745, DOI: 10.1038/s41593-018-0120-6.Peer-Reviewed Original ResearchConceptsMyelin degenerationYears of ageAge-related degenerationMyelin plasticityMyelin remodelingNeural processing speedBrain pathogenesisOligodendrocyte deathUnmyelinated axonsAxonal myelinMyelin coverageStructural remodelingMouse cortexMammalian brainPeak myelinationOligodendrocyte generationIndividual axonsMyelinating oligodendrocytesMyelin distributionDegenerationMyelin internodesNetwork homeostasisAxonsStructural plasticityRemodelingLong-term dendritic spine stability in the adult cortex
Grutzendler J, Kasthuri N, Gan WB. Long-term dendritic spine stability in the adult cortex. Nature 2002, 420: 812-816. PMID: 12490949, DOI: 10.1038/nature01276.Peer-Reviewed Original ResearchConceptsLayer 5 pyramidal neuronsAxo-dendritic synapsesFilopodia-like dendritic protrusionsPrimary visual cortexVisual cortex developmentDendritic spine stabilityTwo-photon imaging techniquePyramidal neuronsDendritic specializationsAdult cortexYoung miceSpine eliminationAdult miceOne-month intervalsNervous systemTransgenic miceSpine stabilityVisual cortexDendritic protrusionsMammalian brainCortex developmentAdult animalsSpineMiceYoung animalsATP mediates rapid microglial response to local brain injury in vivo
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 2005, 8: 752-758. PMID: 15895084, DOI: 10.1038/nn1472.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsApyraseAstrocytesBrainBrain InjuriesCell CommunicationChemotaxisConnexinsGliosisGreen Fluorescent ProteinsMiceMice, TransgenicMicrogliaPhagocytosisPurinergic P2 Receptor AntagonistsReaction TimeReceptors, Purinergic P2Receptors, Purinergic P2Y1Signal TransductionConceptsRapid microglial responseMicroglial processesMicroglial responseBrain injuryG protein-coupled purinergic receptorsLocal brain injuryTraumatic brain injurySite of injuryPrincipal immune cellsPresence of apyraseParenchymal microgliaImmune cellsLocal injectionPurinergic receptorsBaseline motilityIntact brainTwo-photon imagingChannel inhibitorsMouse cortexInjuryExtracellular ATPMicrogliaEnzyme apyraseAstrocytesChemotactic responseMicroglia 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 ResearchIn vivo imaging of oligodendrocytes with sulforhodamine 101
Hill RA, Grutzendler J. In vivo imaging of oligodendrocytes with sulforhodamine 101. Nature Methods 2014, 11: 1081-1082. PMID: 25357236, PMCID: PMC4539948, DOI: 10.1038/nmeth.3140.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
2022
Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death
Aber ER, Griffey CJ, Davies T, Li AM, Yang YJ, Croce KR, Goldman JE, Grutzendler J, Canman JC, Yamamoto A. Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death. Cell Reports 2022, 41: 111480. PMID: 36261002, PMCID: PMC9639605, DOI: 10.1016/j.celrep.2022.111480.Peer-Reviewed Original ResearchConceptsCell typesLive-cell imagingNeurodegenerative disease pathophysiologySuch cell typesMouse geneticsAdult-onset neurodegenerative diseaseMacroautophagyCell imagingNeurodegenerative diseasesMyelin proteinsNeurodegenerationDisease pathophysiologyTurnoverMature oligodendrocytesCentral nervous systemAmphisomesMyelin sheath structureNeural functionNervous systemMyelin turnoverGeneticsMyelin sheathProgressive motor declineProteinHomeostasisKCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling
Ando K, Tong L, Peng D, Vázquez-Liébanas E, Chiyoda H, He L, Liu J, Kawakami K, Mochizuki N, Fukuhara S, Grutzendler J, Betsholtz C. KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling. Developmental Cell 2022, 57: 1383-1399.e7. PMID: 35588738, DOI: 10.1016/j.devcel.2022.04.019.Peer-Reviewed Original ResearchConceptsK-ATP channel functionVascular smooth muscle cell differentiationChannel functionSmooth muscle cell differentiationMuscle cell differentiationVascular smooth muscle developmentSmooth muscle developmentVSMC developmentHuman central nervous system disordersMuscle developmentVSMC differentiationCentral nervous system disordersCell differentiationChemical inhibitionVoltage-dependent calcium channelsATP-sensitive potassium channelsFunction mutationsCell progenitorsK-ATP channelsCerebral blood flowCell culture modelMolecular causesNervous system disordersIntracellular CaVasoconstrictive capacity
2021
Intravital Imaging of Neocortical Heterotopia Reveals Aberrant Axonal Pathfinding and Myelination around Ectopic Neurons
Li AM, Hill RA, Grutzendler J. Intravital Imaging of Neocortical Heterotopia Reveals Aberrant Axonal Pathfinding and Myelination around Ectopic Neurons. Cerebral Cortex 2021, 31: 4340-4356. PMID: 33877363, PMCID: PMC8328209, DOI: 10.1093/cercor/bhab090.Peer-Reviewed Original ResearchConceptsNeuronal clustersEarly postnatal developmentVivo calcium imagingEctopic neuronal clustersAxonal patternNeocortical heterotopiaHeterotopic neuronsCortical heterotopiaHeterotopia formationEctopic neuronsAnimal modelsTractable animal modelPostnatal developmentCalcium imagingBrain regionsInducible modelIntravital imagingNeuronsAxonal pathfindingAberrant patternsHeterotopiaMyelinationAxon guidanceCognitive disabilitiesLive mice
2018
Flexible Learning-Free Segmentation and Reconstruction of Neural Volumes
Shahbazi A, Kinnison J, Vescovi R, Du M, Hill R, Joesch M, Takeno M, Zeng H, da Costa NM, Grutzendler J, Kasthuri N, Scheirer WJ. Flexible Learning-Free Segmentation and Reconstruction of Neural Volumes. Scientific Reports 2018, 8: 14247. PMID: 30250218, PMCID: PMC6155135, DOI: 10.1038/s41598-018-32628-3.Peer-Reviewed Original ResearchConceptsGigabytes of dataSupervised learning methodsHigh-energy synchrotron X-ray microtomographyHigh-quality reconstructionComputer visionHigh biological fidelityVirtual eyeSpectral confocal reflectance microscopyStack of imagesLearning methodsPipeline reconstructionContextual cluesDifferent modalitiesNeural volumeMouse datasetsBiological fidelityImagesData collectionPipelineGigabytesSegmentationMachineAlgorithmDatasetSufficient qualityActivation of pial and dural macrophages and dendritic cells by cortical spreading depression
Schain AJ, Melo‐Carrillo A, Borsook D, Grutzendler J, Strassman AM, Burstein R. Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Annals Of Neurology 2018, 83: 508-521. PMID: 29394508, PMCID: PMC5965700, DOI: 10.1002/ana.25169.Peer-Reviewed Original ResearchConceptsBlood-brain barrierDendritic cellsDural macrophagesImmune cellsAnatomical relationshipMigratory dendritic cellsAnn NeurolTRPV1 axonsMeningeal nociceptorsHead painMigraine attacksNociceptor activationSubarachnoid spaceMeningeal macrophagesMacrophagesCortical eventsAxonsActivationAuraDuraDepressionMinutesCellsCellular eventsCSD
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