Transcriptional Signatures of Tau and Amyloid Neuropathology

Castanho, Isabel; Murray, Tracey K.; Hannon, Eilís; Jeffries, Aaron R.; Walker, Emma; Laing, Emma M.; Baulf, Hedley; Harvey, Joshua; Bradshaw, Lauren; Randall, Andrew; Moore, Karen; O’Neill, Paul; Lunnon, Katie; Collier, David A.; Ahmed, Zeshan; O’Neill, Michael; Mill, Jonathan

doi:10.1016/j.celrep.2020.01.063

Cited by 57 publications

(72 citation statements)

References 76 publications

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“…While aging has myriad systemic and cellular targets, one key emerging theme is the dysregulation of innate immune mechanisms leading to a systemic pro-inflammatory state, which has been termed “immunosenescence” or “inflamm-ageing” [ 65 , 66 ]. In our analysis, innate immune pathways were strongly enriched among both aging- and Tau-associated, differentially expressed genes, and this result is consistent with brain gene expression profiling in mouse models of healthy aging [ 10 , 67 ] and tauopathy [ 68 , 69 ]. Similarly, multiple transcriptome- and proteome-wide analyses of human postmortem brain from AD or other tauopathies, such as PSP, have identified evidence of dysregulated immune pathways [ 9 – 11 , 18 ], and similar signatures have been implicated in brains from aged individuals without known neurodegenerative disease [ 70 , 71 ].…”

Section: Discussionsupporting

confidence: 85%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Mol Neurodegeneration

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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 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. Results TauWT 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. 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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Section: Discussionsupporting

confidence: 85%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Mol Neurodegeneration

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“…While aging has myriad systemic and cellular targets, one key emerging theme is the dysregulation of innate immune mechanisms leading to a systemic pro-inflammatory state, which has been termed "immunosenescence" or "inflamm-ageing" [58,59]. In our analysis, innate immune pathways were strongly enriched among both aging-and Tau-associated, differentially expressed genes, and this result is consistent with brain gene expression profiling in mouse models of healthy aging [23,60] and tauopathy [61,62]. Similarly, multiple transcriptome-and proteome-wide analyses of human postmortem brain from AD or other tauopathies, such as PSP, have identified evidence of dysregulated immune pathways [9][10][11]18], and similar signatures have been implicated in brains from aged individuals without known neurodegenerative disease [63,64].…”

Section: Discussionsupporting

confidence: 83%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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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...

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“…We do observe some reciprocal relationships between human tau transgene overexpression (driven by a truncated form of the CAMKIIα promoter) and endogenous mouse tau, which remain largely unexplained. A recent report on the entorhinal cortex of rTg4510 animals, shows that mouse MAPT expression remained unaltered in diseased animals, while human MAPT increased drastically; a result consistent through ages of 2 to 8 months [10]. Our data adds a level of complexity to these results by showing alterations of these genes in NFT bearing neurons of 12 months old animals, with a decrease in the expression of human MAPT and an increase in mouse MAPT.…”

Section: Discussionsupporting

confidence: 80%

“…Doing so, we were able to distinguish the effects of transgene overexpression and tau aggregation. We hypothesized that neurons that develop tau aggregation but without the consequences of overexpressing human tau, may better reflect Tau overexpression has multiple effects on gene expression measured by bulk analyses in the tg4510 mouse [10]. However, as the animals age there is dramatic neurodegeneration and glial activation [24].…”

Section: Discussionmentioning

confidence: 99%

Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds

Pérez-Rando

Dujardin

Bennett

et al. 2020

acta neuropathol commun

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Recent studies suggest that misfolded tau molecules can be released, and taken up by adjacent neurons, propagating proteopathic seeds across neural systems. Yet critical to understanding whether tau propagation is relevant in pathophysiology of disease would be to learn if it alters neuronal properties. We utilized high resolution multi-color in situ hybridization technology, RNAScope, in a well-established tau transgenic animal, and found that a subset of neurons in the cortex do not appear to express the transgene, but do develop phospho-tau positive inclusions, consistent with having received tau seeds. Recipient neurons show decreases in their expression of synaptophysin, CAMKIIα, and mouse tau in both young and old animals. These results contrast with neurons that develop tau aggregates and also overexpress the transgene, which have few changes in expression of metabolic and synaptic markers. Taken together, these results strongly suggest that tau propagation impacts neuronal functional integrity.

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Transcriptional Signatures of Tau and Amyloid Neuropathology

Cited by 57 publications

References 76 publications

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds

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