Integrated analysis of the aging brain transcriptome and proteome in tauopathy

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 agedependent 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 (Tau WT ) or a mutation 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. ResultsTau WT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. Tau R406W 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. 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. BackgroundThe Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer's disease (AD) and other neurodegenerative tauopathies characterized by progressive cognitive and/or motor disability, including progressive supranuclear palsy (PSP), corticobasal degeneration, chronic traumatic encephalopathy, and certain forms of frontotemporal dementia (FTD) [1,2]. Rare mutations in the MAPT gene cause familial FTD, which is also characterized by prominent neurofibrillary tangle deposition [3][4][5]. Based on this genetic evidence, along with results from cellular and animal models [6,7], Tau is a critical mediator of age-related neurodegeneration and a causal link among this diverse group of neurologic disorders. While the precise mechanisms of Tauinduced neuronal injury remain incompletely defined, progressive synaptic dysfunction and neuronal loss likely arises from a cascade of cellular derangements, including oxidative-and immune-mediated injury, altered proteostasis, and aberrant transcription and translation [6,8].RNA-sequencing (RNA-seq) makes possible comprehensive gene expression profiling of postmortem human brain tissue in AD and o...

Tau polarizes an aging transcriptional signature to excitatory neurons and glia

“…The increased intensity of antibody staining in tau brains may arise from enhanced antibody penetration, since similar changes are also seen for other markers (Figure S6B). Moreover, increased repo gene expression was not observed in either scRNAseq or in our previously published bulk-tissue RNAseq (Mangleburg et al, 2020). Overall, our results suggest that the apparent increase in glial cell abundance from scRNAseq is likely a consequence of proportional changes in single cell suspensions due to neuronal loss.…”

“…Genes encoding regulators of immunity, including TREM2, CR1, and many others, have been strongly implicated in AD susceptibility by human genetics (Bellenguez et al, 2022), and abundant evidence now supports a key role for many such genes among glial cells (Wang et al, 2015;Zhou et al, 2020;Keren-Shaul et al, 2017). We previously identified an age-associated Drosophila innate immune response signature that is amplified by tau (Mangleburg et al, 2020). Here, we significantly extend these observations, leveraging the cellular resolution afforded by single cell profiles.…”

Rapid Cell Type-Specific Nascent Proteome Labeling in Drosophila

“…Major insights from these studies highlight strong conservation with mammalian biology and have spurred diverse proteomic analyses of gene expression in the fly nervous system (21,(32)(33)(34) and interest in using flies to model the role of translational regulation in nervous system disease (35)(36)(37). In addition to the work on diseases such as fragile X syndrome (35), frontotemporal dementia (37) and diseases associated with aminoacyl-tRNA synthetase mutations (36) by others, we recently showed how aberrant translation contributes to neurodegenerative phenotypes caused by the common Parkinson's disease-causing mutation LRRK2 G2019S in Drosophila and iPSC-derived dopamine neurons (38)(39)(40), adding to emerging evidence of translational dysregulation in models of Parkinson's disease (41).…”

Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?

“…Studies in Drosophila melanogaster, for instance, can also draw from a rich set of aging-associated phenotypic changes, which can be utilized collectively as a proxy to measure aging. This includes, but is not limited to, analyses of molecular alterations (e.g., bulk changes in transcriptome [172][173][174][175], proteome [176,177] and metabolome [178,179]; single-cell transcriptomic changes [180]); neuromorphological changes (e.g., neurodegeneration [181]), behavioral assessments (e.g., learning and memory [182][183][184], locomotor activity [185,186], circadian rhythm and sleep patterns [187,188]), an assessment of muscle structure and function (e.g., changes in muscle morphology and integrity [189]), analyses of changes in heart function (e.g., assessment of cardiac performance [190,191]) and gut homeostasis (e.g., histopathological analyses of epithelial dysplasia and barrier function [91]).…”