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Integrated analysis of the aging brain transcriptome and proteome in tauopathy

By Carl Grant Mangleburg, Timothy Wu, Hari K. Yalamanchili, Caiwei Guo, Yi-Chen Hsieh, Duc M. Duong, Eric B. Dammer, Philip L De Jager, Nicholas T. Seyfried, Zhandong Liu, Joshua M. Shulman

Posted 20 Feb 2020
bioRxiv DOI: 10.1101/2020.02.19.954578

Background Tau neurofibrillary tangle pathology characterizes Alzheimer 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. Methods Paired, 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. Results TauWT 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. Conclusions Our 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.

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