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 ResearchMeSH KeywordsAlzheimer DiseaseAnimalsAxonsDisease Models, AnimalMicePhospholipase DSpheroids, CellularConceptsAxonal 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 mannerDysfunctionTREM2 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 fibrilsHaplodeficiencyPlaquesDiseaseDystrophy
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
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
TREM2-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 ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsDisease Models, AnimalHumansMembrane GlycoproteinsMiceMice, KnockoutMicrogliaMonocytesNeuritesReceptors, ImmunologicConceptsAlzheimer'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 debateMicrogliaAttenuation 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
Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques
Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e3699-e3708. PMID: 26124111, PMCID: PMC4507205, DOI: 10.1073/pnas.1510329112.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid Precursor Protein SecretasesAnimalsAspartic Acid EndopeptidasesAxonsDisease Models, AnimalLysosomesMembrane ProteinsMicePlaque, AmyloidConceptsAmyloid plaquesNeuronal lysosomesAlzheimer's diseaseAlzheimer's disease brain pathologyLysosome accumulationAlzheimer's disease (AD) amyloid plaquesΒ-amyloid depositionΒ-amyloid depositsAmyloid precursor proteinLysosome-like organellesRetrograde axonal transportWild-type brainsSuch axonsSwollen axonsMassive accumulationAxonal lysosomesBrain pathologyAmyloidogenic processingMouse modelAmyloid depositsLuminal proteasesAxonal transportLocal impairmentNeuronal processesNeurodegenerative diseases
2011
Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition
Condello C, Schain A, Grutzendler J. Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Scientific Reports 2011, 1: 19. PMID: 22355538, PMCID: PMC3216507, DOI: 10.1038/srep00019.Peer-Reviewed Original ResearchConceptsPlaque burdenAmyloid depositionAlzheimer's diseaseAD mouse modelPlaque enlargementClinicopathological studyNeuritic dystrophyPathogenic rolePostmortem studiesAmyloid plaquesNew plaquesConsequent neurotoxicityMouse modelOld plaquesQuantitative confocal imagingCognitive statusPlaquesPlaque expansionOld animalsAmyloid-binding dyesNeurotoxicityDiseasePoor correlationBurdenCritical determinant