Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Background: Tau 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. Methods: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in aDrosophilamodel of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau(WT)) or a mutant form causing frontotemporal dementia (Tau(R406W)). 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: Tau(WT)induced 1514 and 213 differentially expressed transcripts and proteins, respectively. Tau(R406W)had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a similar to 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. 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.