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Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

Author

Listed:
  • Zoeb Jiwaji

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Sachin S. Tiwari

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • Rolando X. Avilés-Reyes

    (University of Wisconsin-Madison)

  • Monique Hooley

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • David Hampton

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • Megan Torvell

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building
    UK Dementia Research Institute at Cardiff University, Hadyn Ellis Building)

  • Delinda A. Johnson

    (University of Wisconsin-Madison)

  • Jamie McQueen

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Paul Baxter

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Kayalvizhi Sabari-Sankar

    (University of Wisconsin-Madison)

  • Jing Qiu

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Xin He

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Jill Fowler

    (University of Edinburgh, Hugh Robson Building, George Square)

  • James Febery

    (University of Edinburgh, Hugh Robson Building, George Square)

  • Jenna Gregory

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • Jamie Rose

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Jane Tulloch

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Jamie Loan

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • David Story

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • Karina McDade

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School)

  • Amy M. Smith

    (Burlington Danes Building, Hammersmith Hospital)

  • Peta Greer

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Matthew Ball

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Peter C. Kind

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Paul M. Matthews

    (Burlington Danes Building, Hammersmith Hospital)

  • Colin Smith

    (University of Edinburgh Chancellor’s Building)

  • Owen Dando

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square
    University of Edinburgh, Hugh Robson Building, George Square)

  • Tara L. Spires-Jones

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

  • Jeffrey A. Johnson

    (University of Wisconsin-Madison)

  • Siddharthan Chandran

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh Chancellor’s Building)

  • Giles E. Hardingham

    (UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School
    University of Edinburgh, Hugh Robson Building, George Square)

Abstract

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

Suggested Citation

  • Zoeb Jiwaji & Sachin S. Tiwari & Rolando X. Avilés-Reyes & Monique Hooley & David Hampton & Megan Torvell & Delinda A. Johnson & Jamie McQueen & Paul Baxter & Kayalvizhi Sabari-Sankar & Jing Qiu & Xin, 2022. "Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27702-w
    DOI: 10.1038/s41467-021-27702-w
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    References listed on IDEAS

    as
    1. Hansruedi Mathys & Jose Davila-Velderrain & Zhuyu Peng & Fan Gao & Shahin Mohammadi & Jennie Z. Young & Madhvi Menon & Liang He & Fatema Abdurrob & Xueqiao Jiang & Anthony J. Martorell & Richard M. Ra, 2019. "Author Correction: Single-cell transcriptomic analysis of Alzheimer’s disease," Nature, Nature, vol. 571(7763), pages 1-1, July.
    2. Hansruedi Mathys & Jose Davila-Velderrain & Zhuyu Peng & Fan Gao & Shahin Mohammadi & Jennie Z. Young & Madhvi Menon & Liang He & Fatema Abdurrob & Xueqiao Jiang & Anthony J. Martorell & Richard M. Ra, 2019. "Single-cell transcriptomic analysis of Alzheimer’s disease," Nature, Nature, vol. 570(7761), pages 332-337, June.
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