Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Molecular Neurodegeneration

Philip L. De Jager¹  Eric B. Dammer²  Duc M. Duong²  Nicholas T. Seyfried³  Yi-Chen Hsieh⁴  Hari K. Yalamanchili⁴  Joshua M. Shulman⁵  Timothy Wu⁶  Carl Grant Mangleburg⁶  Caiwei Guo⁷  Zhandong Liu⁸ 

[1] Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the study of Alzheimer’s disease and the aging brain, Columbia University Medical Center, 10032, New York, NY, USA;Cell Circuits Program, Broad Institute, 02142, Cambridge, MA, USA;Department of Biochemistry, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Biochemistry, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Neurology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Neuroscience, Baylor College of Medicine, 77030, Houston, TX, USA;Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, 1250 Moursund St., Suite N.1150, 77030, Houston, TX, USA;Department of Neurology, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, 77030, Houston, TX, USA;Medical Scientist Training Program, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Neuroscience, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Pediatrics, Baylor College of Medicine, 77030, Houston, TX, USA;Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, 1250 Moursund St., Suite N.1150, 77030, Houston, TX, USA;

关键词: MAPT;    Tau;    Alzheimer’s disease;    Transcriptome;    Proteome;    Inflammation;    Innate immunity;   

DOI  :  10.1186/s13024-020-00405-4

来源: Springer

【 摘 要 】

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 mutant form 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 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 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. 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.

【 授权许可】

CC BY