Journal
MOLECULAR NEURODEGENERATION
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13024-020-00405-4
Keywords
MAPT; Tau; Alzheimer's disease; Transcriptome; Proteome; Inflammation; Innate immunity
Categories
Funding
- NIH [R01AG053960, R01AG050631, R01AG057339, U01AG061357, U01AG046161, R01AG057911, R01AG061800, RF1AG057471, RF1AG057470]
- Cullen Foundation
- Baylor College of Medicine Medical Scientist Training Program (MSTP)
- Cancer Prevention Research Institute of Texas [RP170387]
- Houston Endowment
- Huffington Foundation
- Belfer Neurodegenerative Disease Consortium
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
- Burroughs Wellcome Fund
- NATIONAL INSTITUTE ON AGING [F31AG067677] Funding Source: NIH RePORTER
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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.
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