Single cell transcriptomic profiling of tauopathy in a novel 3D neuron-astrocyte coculture model
Single cell transcriptomic profiling of tauopathy in a novel 3D neuron-astrocyte coculture model
ABSTRACT The use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte spheroids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 was used to address the putative dysfunctional HSP chaperone system and produced a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.
Medalla Maria、Wolozin Benjamin、Rickner Hannah Drew、Snyder Benjamin J、Zhang Lushuang、Mojica Chromewell A、Shaw Dipan、Cheng Christine S.、Hong Rui、O?ˉNeill Nicholas K、Jiang Lulu
Department of Anatomy & Neurobiology, Boston University School of Medicine||Center for Systems Neuroscience, Boston UniversityDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine||Department of Neurology, Boston University School of Medicine Benjamin Wolozin||Center for Systems Neuroscience, Boston UniversityDepartment of Biology, Boston UniversityDepartment of Anatomy & Neurobiology, Boston University School of MedicineDepartment of Pharmacology and Experimental Therapeutics, Boston University School of MedicineDepartment of Anatomy & Neurobiology, Boston University School of MedicineInformatics Group, J. Craig Venter InstituteDepartment of Biology, Boston University||Program in Bioinformatics, Boston University||Informatics Group, J. Craig Venter Institute||Department of Psychiatry, University of California San DiegoProgram in Bioinformatics, Boston UniversityProgram in Bioinformatics, Boston UniversityDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine
神经病学、精神病学基础医学细胞生物学
Pluripotent stem cells3D culturedisease modelingneurodegenerative diseasestauopathyphospho-tauneuronsastrocytesreactive astrogliosiscell deathheat shock protein chaperonesingle cell transcriptomics
Medalla Maria,Wolozin Benjamin,Rickner Hannah Drew,Snyder Benjamin J,Zhang Lushuang,Mojica Chromewell A,Shaw Dipan,Cheng Christine S.,Hong Rui,O?ˉNeill Nicholas K,Jiang Lulu.Single cell transcriptomic profiling of tauopathy in a novel 3D neuron-astrocyte coculture model[EB/OL].(2025-03-28)[2025-05-22].https://www.biorxiv.org/content/10.1101/2022.05.03.490513.点此复制
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