Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Abstract BackgroundTau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutation causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. ResultsTauWT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.
Guo Caiwei、Duong Duc M.、De Jager Philip L.、Mangleburg Carl Grant、Liu Zhandong、Shulman Joshua M.、Wu Timothy、Dammer Eric B.、Hsieh Yi-Chen、Yalamanchili Hari K.、Seyfried Nicholas T.
Department of Neuroscience, Baylor College of MedicineDepartment of Biochemistry, Emory University School of MedicineCenter for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the study of Alzheimer?ˉs disease and the aging brain, Columbia University Medical Center||Cell Circuits Program, Broad InstituteDepartment of Molecular and Human Genetics, Baylor College of Medicine||Medical Scientist Training Program, Baylor College of MedicineDepartment of Pediatrics, Baylor College of Medicine||Jan and Dan Duncan Neurological Research InstituteDepartment of Molecular and Human Genetics, Baylor College of Medicine||Department of Neuroscience, Baylor College of Medicine||Jan and Dan Duncan Neurological Research Institute||Department of Neurology, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of Medicine||Medical Scientist Training Program, Baylor College of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Biochemistry, Emory University School of Medicine||Department of Neurology, Emory University School of Medicine
神经病学、精神病学生物科学研究方法、生物科学研究技术基础医学
MAPTTauAlzheimer’s diseasetranscriptomeproteomeinflammationinnate immunity
Guo Caiwei,Duong Duc M.,De Jager Philip L.,Mangleburg Carl Grant,Liu Zhandong,Shulman Joshua M.,Wu Timothy,Dammer Eric B.,Hsieh Yi-Chen,Yalamanchili Hari K.,Seyfried Nicholas T..Integrated analysis of the aging brain transcriptome and proteome in tauopathy[EB/OL].(2025-03-28)[2025-05-10].https://www.biorxiv.org/content/10.1101/2020.02.19.954578.点此复制
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