2025
Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain
Cai Y, Pinheiro-de-Sousa I, Slobodyanyuk M, Chen F, Huynh T, Kanyo J, Tang P, Fuentes L, Braker A, Welch R, Huttner A, Tong L, Yuan P, Lam T, Petsalaki E, Reimand J, Nairn A, Grutzendler J. Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain. Nature Neuroscience 2025, 1-18. PMID: 40514588, DOI: 10.1038/s41593-025-01973-8.Peer-Reviewed Original ResearchSubcellular proteomicsAlzheimer's diseaseFemale 5XFAD miceProteomic hitsSubcellular localizationAmyloid-bProtein aggregationLigand-receptor interactionsAD donorsLipid metabolismExpansion microscopyPostmortem human brainProteomicsAxonal outgrowthMouse brainAlzheimerNeuronal plasticityCritical sitesAberrant myelinationMyelin ensheathmentDystrophic axonsMetabolic supportMiceAxonal structureMetabolismMultimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI
Mandino F, Horien C, Shen X, Desrosiers-Grégoire G, Luo W, Markicevic M, Constable R, Papademetris X, Chakravarty M, Betzel R, Lake E. Multimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI. Communications Biology 2025, 8: 665. PMID: 40287579, PMCID: PMC12033268, DOI: 10.1038/s42003-025-08037-4.Peer-Reviewed Original ResearchConceptsBOLD fMRIBOLD fMRI dataConnectome-based identificationCognitive neuroscientistsFMRI literatureHeterogeneous neurological conditionsWhole cortexFMRIMouse brainSimultaneous Ca2+ imagingCa2+ imagingAnimal modelsFluorescence calcium imagingCalcium imagingNeurological conditionsPersonalized treatmentNeuroimagingBOLDCortexNeuroscientistsBrainMiceMultimodal identificationCell-type specific signalsSubcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Cai Y, Kanyo J, Wilson R, Bathla S, Cardozo P, Tong L, Qin S, Fuentes L, Pinheiro-de-Sousa I, Huynh T, Sun L, Mansuri M, Tian Z, Gan H, Braker A, Trinh H, Huttner A, Lam T, Petsalaki E, Brennand K, Nairn A, Grutzendler J. Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease. Nature Aging 2025, 5: 504-527. PMID: 40065072, PMCID: PMC11922768, DOI: 10.1038/s43587-025-00823-3.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseProximity labeling approachIPSC-derived neuronsSubcellular proteomicsCytoskeleton dynamicsPhosphorylated mTOR levelsDystrophic neuritesLipid transportBiological processesProtein turnoverAD modelHuman induced pluripotent stem cellsAmyloid depositsIPSC modelsProteomicsInduced pluripotent stem cellsPluripotent stem cellsMTOR inhibitionTherapeutic targetAxonal pathologyLabeling approachMTOR levelsMouse brainSpheroid formationAlzheimerHuman and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome
Yarbro J, Han X, Dasgupta A, Yang K, Liu D, Shrestha H, Zaman M, Wang Z, Yu K, Lee D, Vanderwall D, Niu M, Sun H, Xie B, Chen P, Jiao Y, Zhang X, Wu Z, Chepyala S, Fu Y, Li Y, Yuan Z, Wang X, Poudel S, Vagnerova B, He Q, Tang A, Ronaldson P, Chang R, Yu G, Liu Y, Peng J. Human and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome. Nature Communications 2025, 16: 1533. PMID: 39934151, PMCID: PMC11814087, DOI: 10.1038/s41467-025-56853-3.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseProtein turnoverMouse model of amyloidosisMulti-omics analysisMurine model of Alzheimer's diseaseModel of Alzheimer's diseaseModel of amyloidosisProteome turnoverMouse proteomeGenetic incorporationAD pathwayAmyloid formationBrain proteomeMulti-OmicsProteomic strategyAD progressionProteomicsProtein alterationsProteinDisease mechanismsAmyloidPathwayPotential targetMouse brainTurnover
2024
Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation
Bierman R, Dave J, Greif D, Salzman J. Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation. ELife 2024, 12: rp87517. PMID: 39699003, PMCID: PMC11658768, DOI: 10.7554/elife.87517.Peer-Reviewed Original ResearchConceptsSubcellular localizationUntranslated regionAlternative poly-adenylationSubcellular RNA localizationCell-type specific regulationLow-throughput studiesUntranslated region lengthRNA subcellular localizationSingle-cell resolutionSpatial transcriptomics techniquesRNA localizationFunction predictionPoly-adenylationTranscriptomic techniquesCellular functionsMouse brainSpecific regulationStatistical frameworkIsoform expressionMouse liverRegulationMiceUntranslatedLocalizationRNAStatistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation
Bierman R, Dave J, Greif D, Salzman J. Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation. ELife 2024, 12 DOI: 10.7554/elife.87517.2.Peer-Reviewed Original ResearchSubcellular localizationUntranslated regionAlternative poly-adenylationSubcellular RNA localizationCell-type specific regulationLow-throughput studiesUntranslated region lengthRNA subcellular localizationSingle-cell resolutionSpatial transcriptomics techniquesRNA localizationFunction predictionPoly-adenylationTranscriptomic techniquesCellular functionsMouse brainSpecific regulationStatistical frameworkIsoform expressionMouse liverRegulationNXPH1MiceUntranslatedLocalizationExploration of (R)-[11C]YH168 as a PET tracer for imaging monoacylglycerol lipase in the brain: from mice to non-human primates
He Y, Zheng M, Gu J, Reichert L, Trimborn J, Zhang H, Keller C, Crosby M, Collin L, Heer D, Pavlovic A, Topp A, Wittwer M, Grether U, Gobbi L, Schibli R, Huang Y, Mu L. Exploration of (R)-[11C]YH168 as a PET tracer for imaging monoacylglycerol lipase in the brain: from mice to non-human primates. European Journal Of Nuclear Medicine And Molecular Imaging 2024, 52: 1556-1565. PMID: 39673602, PMCID: PMC11839854, DOI: 10.1007/s00259-024-07013-0.Peer-Reviewed Original ResearchMonoacylglycerol lipaseNon-human primatesIn vitro autoradiographyBrain regionsMice to non-human primatesMAGL knockoutNon-displaceable binding potentialRhesus monkeysNon-human primate brainRegional non-displaceable binding potentialsRegional time-activity curvesMouse brainCingulate cortexFrontal cortexEndocannabinoid systemLevels of radioactive uptakeMouse brain slicesOccipital cortexBrains of miceOne-tissue compartment modelBinding potentialMAGL expressionPET scansKnockout micePrimate brainProximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions
Gao Y, Shonai D, Trn M, Zhao J, Soderblom E, Garcia-Moreno S, Gersbach C, Wetsel W, Dawson G, Velmeshev D, Jiang Y, Sloofman L, Buxbaum J, Soderling S. Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions. Nature Communications 2024, 15: 6801. PMID: 39122707, PMCID: PMC11316102, DOI: 10.1038/s41467-024-51037-x.Peer-Reviewed Original ResearchConceptsSpatial proteomicsRisk genesHigh-confidence risk genesRegulation of expressionAutism risk genesGenetic interactionsProximity proteomicsHuman genesEndogenous proteomesProtein complexesCellular functionsNative proteomeProteomicsPhenotypic modifiersRisk allelesRelevant to autismGenesFunctional interactionsGenetic riskProteinMouse brainMouse model of autismCellular driversProximity interactionsMouse modelThe loss of βΙ spectrin alters synaptic size and composition in the ja/ja mouse
Stankewich M, Peters L, Morrow J. The loss of βΙ spectrin alters synaptic size and composition in the ja/ja mouse. Frontiers In Neuroscience 2024, 18: 1415115. PMID: 39165342, PMCID: PMC11333264, DOI: 10.3389/fnins.2024.1415115.Peer-Reviewed Original ResearchJa/ja miceGranule layerCerebellar granule layerPostnatal day 8Cortical layers 2Cerebellar granule neuronsPostsynaptic density sizeSpectrin gene familyJaundiced miceMature mouse brainExchange transfusionHemolytic anemiaHemolytic pathologiesHematological consequencesMedial habenulaGranule neuronsFatal hemolytic anemiaDay 8Dentate gyrusNeuropsychiatric disordersSpectrin deficiencyWhite matterJa/jaMiceMouse brainNeurons for infant social behaviors in the mouse zona incerta
Li Y, Liu Z, Santana G, Capaz A, Doumazane E, Gao X, Renier N, Dietrich M. Neurons for infant social behaviors in the mouse zona incerta. Science 2024, 385: 409-416. PMID: 39052814, DOI: 10.1126/science.adk7411.Peer-Reviewed Original ResearchConceptsInfant social behaviorSocial behaviorZona incertaSomatostatin-expressing neuronsNeural basisInfant behaviorBehavioral distressEmotional developmentMaternal presenceNeural activity manipulationFacilitation of learningBrain centersSocial interactionPopulations of neuronsInfant mouse brainPreweaning miceMouse brainNeuronsInfantsMiceActive manipulationBehaviorMothersDistressIncertaTransmembrane pH gradient imaging in rodent glioma models
Mishra S, Santana J, Mihailovic J, Hyder F, Coman D. Transmembrane pH gradient imaging in rodent glioma models. NMR In Biomedicine 2024, 37: e5102. PMID: 38263680, PMCID: PMC10987279, DOI: 10.1002/nbm.5102.Peer-Reviewed Original ResearchNormal tissuesRodent glioma modelsGL261 gliomasU87 gliomasTumor microenvironmentPotential therapeutic targetGlioma modelTumor survivalExtracellular acidosisTumorMetabolic reprogrammingRegulate drug deliveryIntracellular pHRat brainExtracellular pHTherapeutic targetGliomaMouse brainDrug deliveryIntracellular milieuTransmembrane pH gradientBrainSubmillimeter resolutionTissueCells
2023
PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease
Zheng C, Nicholson L, Chen B, Toyonaga T, Liu M, Strittmatter S, Carson R, Huang Y, Cai Z. PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.081695.Peer-Reviewed Original ResearchAPP/PS1 micePS1 miceWT miceCentral nervous systemTime-activity curvesAlzheimer's diseaseAPP/PS1 transgenic miceAPP/PS1 transgenic AD miceMouse brainAge-matched WT controlsPS1 transgenic miceAPP/PS1Transgenic AD miceDynamic PET imaging dataROCK2 protein expressionAD drug discoveryHigh tracer uptakeMin post injectionPET imaging resultsExpression levelsReference tissue model 2PET imaging dataProtein expression levelsAD miceRegional time-activity curvesA guide to the BRAIN Initiative Cell Census Network data ecosystem
Hawrylycz M, Martone M, Ascoli G, Bjaalie J, Dong H, Ghosh S, Gillis J, Hertzano R, Haynor D, Hof P, Kim Y, Lein E, Liu Y, Miller J, Mitra P, Mukamel E, Ng L, Osumi-Sutherland D, Peng H, Ray P, Sanchez R, Regev A, Ropelewski A, Scheuermann R, Tan S, Thompson C, Tickle T, Tilgner H, Varghese M, Wester B, White O, Zeng H, Aevermann B, Allemang D, Ament S, Athey T, Baker C, Baker K, Baker P, Bandrowski A, Banerjee S, Bishwakarma P, Carr A, Chen M, Choudhury R, Cool J, Creasy H, D’Orazi F, Degatano K, Dichter B, Ding S, Dolbeare T, Ecker J, Fang R, Fillion-Robin J, Fliss T, Gee J, Gillespie T, Gouwens N, Zhang G, Halchenko Y, Harris N, Herb B, Hintiryan H, Hood G, Horvath S, Huo B, Jarecka D, Jiang S, Khajouei F, Kiernan E, Kir H, Kruse L, Lee C, Lelieveldt B, Li Y, Liu H, Liu L, Markuhar A, Mathews J, Mathews K, Mezias C, Miller M, Mollenkopf T, Mufti S, Mungall C, Orvis J, Puchades M, Qu L, Receveur J, Ren B, Sjoquist N, Staats B, Tward D, van Velthoven C, Wang Q, Xie F, Xu H, Yao Z, Yun Z, Zhang Y, Zheng W, Zingg B. A guide to the BRAIN Initiative Cell Census Network data ecosystem. PLOS Biology 2023, 21: e3002133. PMID: 37390046, PMCID: PMC10313015, DOI: 10.1371/journal.pbio.3002133.Peer-Reviewed Original ResearchSpatial epigenome–transcriptome co-profiling of mammalian tissues
Zhang D, Deng Y, Kukanja P, Agirre E, Bartosovic M, Dong M, Ma C, Ma S, Su G, Bao S, Liu Y, Xiao Y, Rosoklija G, Dwork A, Mann J, Leong K, Boldrini M, Wang L, Haeussler M, Raphael B, Kluger Y, Castelo-Branco G, Fan R. Spatial epigenome–transcriptome co-profiling of mammalian tissues. Nature 2023, 616: 113-122. PMID: 36922587, PMCID: PMC10076218, DOI: 10.1038/s41586-023-05795-1.Peer-Reviewed Original ResearchConceptsGene expressionSingle-cell resolutionChromatin accessibilityJoint profilingHistone modificationsGene regulationCellular statesEpigenetic mechanismsCentral dogmaSpatial transcriptomeTranscriptional phenotypeCell statesOmics informationSpatial transcriptomicsEpigenetic primingMammalian tissuesEpigenomeMolecular biologyTissue architectureCell dynamicsMechanistic relationshipDifferential rolesNew insightsMouse brainProfilingNeonatal loss of FGFR2 in astroglial cells affects locomotion, sociability, working memory, and glia-neuron interactions in mice
Stevens H, Scuderi S, Collica S, Tomasi S, Horvath T, Vaccarino F. Neonatal loss of FGFR2 in astroglial cells affects locomotion, sociability, working memory, and glia-neuron interactions in mice. Translational Psychiatry 2023, 13: 89. PMID: 36906620, PMCID: PMC10008554, DOI: 10.1038/s41398-023-02372-y.Peer-Reviewed Original ResearchConceptsFibroblast growth factor receptor 2Anxiety-like behaviorAttention deficit hyperactivity disorderAstroglial cellsGrowth factor receptor 2Reduced anxiety-like behaviorGlia-neuron interactionsAstroglial cell functionEarly postnatal periodFactor receptor 2Early postnatal lossPostnatal mouse brainWeeks of ageDeficit hyperactivity disorderGlial cellsGlutamine synthetase expressionBehavioral deficitsPostnatal periodReceptor 2Floxed miceHGFAP-CreMouse brainNeonatal lossPostnatal astrogliaPostnatal loss18F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging
An X, Wang J, Tong L, Zhang X, Fu H, Zhang J, Xie H, Huang Y, Jia H. 18F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging. Bioorganic & Medicinal Chemistry 2023, 83: 117233. PMID: 36933438, DOI: 10.1016/j.bmc.2023.117233.Peer-Reviewed Original ResearchConceptsBrain of lipopolysaccharideMale ICR miceModerate brain uptakeFactor 1 receptorColony-stimulating factor 1 receptorBrain uptakeICR miceGBq/Metabolic stability studiesID/Neuroinflammation imagingMouse brainBiodistribution studiesNanomolar inhibitory potencyReceptor ligandsMiceInhibitory potencySpecific bindingBrainCSF-1RRadiochemical purityMolar activityDisorder of Golgi Apparatus Precedes Anoxia-Induced Pathology of Mitochondria
Morozov Y, Rakic P. Disorder of Golgi Apparatus Precedes Anoxia-Induced Pathology of Mitochondria. International Journal Of Molecular Sciences 2023, 24: 4432. PMID: 36901863, PMCID: PMC10003327, DOI: 10.3390/ijms24054432.Peer-Reviewed Original ResearchConceptsGolgi apparatusH anoxiaPost-translational protein modificationStomatin-like protein 2Role of mitochondriaEmbryonic mouse brainEmbryonic mouse brain cellsGolgi architectureSecretory traffickingMitochondrial matrixProtein modificationMouse brain cellsMitochondrial malfunctionTrans cisternaeBrain cellsMitochondriaOrganellesProtein 2Mitochondrial disordersLateral ganglionic eminenceEarly eventsComplex pathological changesMouse brainNormal ultrastructureGanglionic eminence
2022
White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology
Jindachomthong K, Yang C, Huang Y, Coman D, Rapanelli M, Hyder F, Dougherty J, Frick L, Pittenger C. White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology. Frontiers In Molecular Neuroscience 2022, 15: 1037481. PMID: 36504678, PMCID: PMC9731796, DOI: 10.3389/fnmol.2022.1037481.Peer-Reviewed Original ResearchTourette syndromeDiffusion tensor imagingDorsal striatumKnockout miceFractional anisotropyCortico-basal ganglia circuitryHDC knockout miceWhite matter abnormalitiesIntact mouse brainBiosynthesis of histamineCortical projectionsNeurochemical abnormalitiesPosterior hypothalamusKO miceVocal ticsFunctional abnormalitiesMyelin productionPathological alterationsDTI literatureOCD pathophysiologyMouse brainBrain regionsKO modelAbnormalitiesTensor imagingAlzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy
Brody AH, Nies SH, Guan F, Smith LM, Mukherjee B, Salazar SA, Lee S, Lam TKT, Strittmatter SM. Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy. Molecular Neurodegeneration 2022, 17: 32. PMID: 35501917, PMCID: PMC9063299, DOI: 10.1186/s13024-022-00526-y.Peer-Reviewed Original ResearchConceptsPS19 miceTau phosphorylationDisease riskPyk2 expressionPyk2 activityHuman neuronal culturesAlzheimer's disease riskNeuro-inflammationSynapse lossTau accumulationTau pathologyMouse survivalC1q depositionT cellsAssociated pathologyMouse modelLittermate controlsMAPK activityHuman neuronsHuman tauNeuronal culturesPyk2 inhibitionVivo modelMouse brainSynaptic functionThe steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract
Zhou Y, Gu B, Brichant G, Singh JP, Yang H, Chang H, Zhao Y, Cheng C, Liu ZW, Alderman MH, Lu L, Yang X, Gao XB, Taylor HS. The steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract. BMC Biology 2022, 20: 93. PMID: 35491423, PMCID: PMC9059368, DOI: 10.1186/s12915-022-01293-4.Peer-Reviewed Original ResearchConceptsEstrogen receptorMaintenance of pregnancyFetal mouse brainReproductive systemE3 micePregnancy outcomesEstrogen actionEstrogen potencyPregnant miceEstrogen exposureEstrogen signalingFetal developmentMouse brainSteroid hormonesUnexpected functional rolesPregnancyReproductive tractHormone estriolBrainReceptorsExpression levelsFetusesExploratory behaviorMiceNovel mechanism
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