1. Genetics and Genomics
  2. Neuroscience

Tau polarizes an aging transcriptional signature to excitatory neurons and glia

  1. Timothy Wu
  2. Jennifer M Deger
  3. Hui Ye
  4. Caiwei Guo
  5. Justin Dhindsa
  6. Brandon T Pekarek
  7. Rami Al-Ouran
  8. Zhandong Liu
  9. Ismael Al-Ramahi
  10. Juan Botas
  11. Joshua M Shulman  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Texas Children's Hospital, United States
https://doi.org/10.7554/eLife.85251
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Cite this article
  1. Timothy Wu
  2. Jennifer M Deger
  3. Hui Ye
  4. Caiwei Guo
  5. Justin Dhindsa
  6. Brandon T Pekarek
  7. Rami Al-Ouran
  8. Zhandong Liu
  9. Ismael Al-Ramahi
  10. Juan Botas
  11. Joshua M Shulman
(2023)
Tau polarizes an aging transcriptional signature to excitatory neurons and glia
eLife 12:e85251.
https://doi.org/10.7554/eLife.85251
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Abstract

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.

Data availability

All original single cell sequencing data have been uploaded to the Accelerating Medicines Parternship (AMP)-AD Knowledge Portal on Synapse and can be accessed through the DOI: https://doi.org/10.7303/syn35798807.1.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Timothy Wu

    Medical Scientist Training Program, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5296-2023

  2. Jennifer M Deger

    Medical Scientist Training Program, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Hui Ye

    Department of Neurology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3965-9702

  4. Caiwei Guo

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Justin Dhindsa

    Medical Scientist Training Program, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Brandon T Pekarek

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Rami Al-Ouran

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhandong Liu

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Ismael Al-Ramahi

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Juan Botas

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5476-5955

  11. Joshua M Shulman

    Department of Neurology, Baylor College of Medicine, Houston, United States
    For correspondence
    joshua.shulman@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1835-1971

Funding

National Institute on Aging (R01AG057339)

  • Zhandong Liu
  • Juan Botas
  • Joshua M Shulman

Huffington Foundation

  • Zhandong Liu
  • Juan Botas
  • Joshua M Shulman

McGee Family Foundation

  • Joshua M Shulman

Duncan Neurological Research Institute

  • Zhandong Liu
  • Ismael Al-Ramahi
  • Juan Botas
  • Joshua M Shulman

Effie Marie Caine Endowed Chair for Alzheimer's Research

  • Joshua M Shulman

National Institute on Aging (R01AG053960)

  • Joshua M Shulman

National Institute on Aging (U01AG061357)

  • Joshua M Shulman

National Institute on Aging (U01AG046161)

  • Joshua M Shulman

Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555)

  • Joshua M Shulman

National Institutes of Health (S10OD023469)

  • Joshua M Shulman

National Institutes of Health (S10OD025240)

  • Joshua M Shulman

Cancer Prevention and Research Institute of Texas (RP200504)

  • Joshua M Shulman

Parkinson's Foundation (PF-PRF-830012)

  • Hui Ye

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Patrik Verstreken, KU Leuven, Belgium

Publication history

  1. Received: November 29, 2022
  2. Accepted: May 22, 2023
  3. Accepted Manuscript published: May 23, 2023 (version 1)

Copyright

© 2023, Wu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Timothy Wu
  2. Jennifer M Deger
  3. Hui Ye
  4. Caiwei Guo
  5. Justin Dhindsa
  6. Brandon T Pekarek
  7. Rami Al-Ouran
  8. Zhandong Liu
  9. Ismael Al-Ramahi
  10. Juan Botas
  11. Joshua M Shulman
(2023)
Tau polarizes an aging transcriptional signature to excitatory neurons and glia
eLife 12:e85251.
https://doi.org/10.7554/eLife.85251

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