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 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.
Highlights
Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies
We identify Tau-induced patterns of differential expression that are robust to adjustment for aging, and we integrate our results with complementary expression profiles from human brains affected by tauopathy and known genetic modifiers of Tau neurotoxicity
Paired tau transcriptomes and proteomes in Drosophila Longitudinal, parallel RNA-seq and mass-spectrometry proteomics were performed in controls and in flies with pan-neuronal expression of human wildtype or mutant Tau
Summary
Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. The Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer’s disease (AD) and other neurodegenerative tauopathies. Emerging evidence suggests that transcription and translation are frequently discordant [16], making it important to consider both mRNA and protein changes to resolve many disease-associated expression signatures. While recent advances in massspectrometry permit deep surveys of protein expression, few studies have systematically profiled both the brain transcriptome and proteome in AD and related tauopathies [17, 18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
