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Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle patho...

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Autores principales: Wu, Timothy, Deger, Jennifer M, Ye, Hui, Guo, Caiwei, Dhindsa, Justin, Pekarek, Brandon T, Al-Ouran, Rami, Liu, Zhandong, Al-Ramahi, Ismael, Botas, Juan, Shulman, Joshua M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259480/
https://www.ncbi.nlm.nih.gov/pubmed/37219079
http://dx.doi.org/10.7554/eLife.85251
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author Wu, Timothy
Deger, Jennifer M
Ye, Hui
Guo, Caiwei
Dhindsa, Justin
Pekarek, Brandon T
Al-Ouran, Rami
Liu, Zhandong
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M
author_facet Wu, Timothy
Deger, Jennifer M
Ye, Hui
Guo, Caiwei
Dhindsa, Justin
Pekarek, Brandon T
Al-Ouran, Rami
Liu, Zhandong
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M
author_sort Wu, Timothy
collection PubMed
description Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
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spelling pubmed-102594802023-06-13 Tau polarizes an aging transcriptional signature to excitatory neurons and glia Wu, Timothy Deger, Jennifer M Ye, Hui Guo, Caiwei Dhindsa, Justin Pekarek, Brandon T Al-Ouran, Rami Liu, Zhandong Al-Ramahi, Ismael Botas, Juan Shulman, Joshua M eLife Genetics and Genomics Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy. eLife Sciences Publications, Ltd 2023-05-23 /pmc/articles/PMC10259480/ /pubmed/37219079 http://dx.doi.org/10.7554/eLife.85251 Text en © 2023, Wu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Wu, Timothy
Deger, Jennifer M
Ye, Hui
Guo, Caiwei
Dhindsa, Justin
Pekarek, Brandon T
Al-Ouran, Rami
Liu, Zhandong
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M
Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title_full Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title_fullStr Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title_full_unstemmed Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title_short Tau polarizes an aging transcriptional signature to excitatory neurons and glia
title_sort tau polarizes an aging transcriptional signature to excitatory neurons and glia
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259480/
https://www.ncbi.nlm.nih.gov/pubmed/37219079
http://dx.doi.org/10.7554/eLife.85251
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