2024
Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism
Takahashi H, Perez-Canamas A, Lee C, Ye H, Han X, Strittmatter S. Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. Communications Biology 2024, 7: 1088. PMID: 39237682, PMCID: PMC11377756, DOI: 10.1038/s42003-024-06810-5.Peer-Reviewed Original ResearchConceptsMyelin lipid metabolismCo-immunoprecipitation assaysSulfated derivative sulfatideLipid metabolismAssociated with multiple neurological disordersCo-immunoprecipitationTMEM106BTransmembrane proteinsAmyloid fibrilsTMEM106B deficiencyHypomyelinating leukodystrophyAlzheimer's diseasePhysiological functionsFrontotemporal dementiaMolecular levelNeurodegenerative brainGalactosylceramidaseLipidomic analysisMultiple neurological disordersMetabolismMyelin lipidsDecreased levelsEndolysosomesAmyloidGalactosylceramidase activityReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Takahashi H, Bhagwagar S, Nies S, Ye H, Han X, Chiasseu M, Wang G, Mackenzie I, Strittmatter S. Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase. Nature Communications 2024, 15: 1434. PMID: 38365772, PMCID: PMC10873339, DOI: 10.1038/s41467-024-45692-3.Peer-Reviewed Original ResearchConceptsTau inclusionsComorbid proteinopathiesTau aggregation in vitroPromotes tau aggregation in vitroAlzheimer's diseaseProgranulin reductionTDP-43 proteinopathyTauopathy phenotypeTau aggregationAD-tauHuman tauopathiesNeurofibrillary tanglesTauopathy miceReduction of progranulinPurified GlcCerTDP-43Concomitant accumulationAggregation in vitroAssociated with synucleinopathiesNeurodegenerative disordersProteinopathiesGCase inhibitionTauGCaseGlcCer
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 ResearchConceptsPositron 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
2021
Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells
Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z, Spajic A, Santpere G, Li M, Zhang S, Liu Y, Spurrier J, Zhang L, Gudelj I, Rapan L, Takahashi H, Huttner A, Fan R, Strittmatter SM, Sousa AMM, Rakic P, Sestan N. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 2021, 110: 452-469.e14. PMID: 34798047, PMCID: PMC8813897, DOI: 10.1016/j.neuron.2021.10.036.Peer-Reviewed Original ResearchConceptsDisease-related proteinsCellular diversityCross-species analysisSingle-nucleus transcriptomesLipid droplet proteinsSpecies-specific propertiesImmature neuron populationTranscriptomic taxonomyAlzheimer's disease-related proteinsEndoplasmic reticulumCell typesHuman neuronsSpecies differencesHistologic signatureNeurogenic capabilityProteinExcitatory neuronsDiversityAdult miceGranule cellsAlzheimer's diseaseNeuron populationsCognitive functionEntorhinal cellsAdult humansSpreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
Nies SH, Takahashi H, Herber CS, Huttner A, Chase A, Strittmatter SM. Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β. Journal Of Biological Chemistry 2021, 297: 101159. PMID: 34480901, PMCID: PMC8477193, DOI: 10.1016/j.jbc.2021.101159.Peer-Reviewed Original ResearchConceptsTau seedsAlzheimer's diseaseAD model miceWT mouse brainPathological tauSynaptic lossTau accumulationWT miceMouse tauTau pathologyTau burdenModel miceTau inclusionsPharmacological interventionsAD riskCognitive declineMouse brainTau aggregatesPyk2 kinaseKnowledge of factorsKinase inhibitorsMiceFyn kinase inhibitorAβMouse aging
2017
Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network
Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM, For the Alzheimer’s Disease Neuroimaging Initiative. Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathologica 2017, 133: 785-807. PMID: 28070672, PMCID: PMC5391267, DOI: 10.1007/s00401-017-1668-z.Peer-Reviewed Original ResearchConceptsAPP/PS1 micePS1 micePGRN deficiencyAlzheimer's diseaseAD risk variantsCerebrospinal fluid Aβ levelsLoss of progranulinMicroglial Aβ phagocytosisCSF tau levelsFrontotemporal lobar degenerationRisk variantsAPPswe/Aβ phagocytosisNeuronal injuryAβ levelsAβ pathologyCerebral amyloidosisAxonal dystrophyTau pathologyTau levelsComplement depositionPGRN levelsAD pathophysiologyAmyloid imagingProgranulin deficiency