IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v568y2019i7751d10.1038_s41586-019-1088-4.html
   My bibliography  Save this article

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

Author

Listed:
  • John V. Pluvinage

    (Stanford University School of Medicine
    Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine
    Stanford University School of Medicine)

  • Michael S. Haney

    (Stanford University School of Medicine)

  • Benjamin A. H. Smith

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Jerry Sun

    (Stanford University School of Medicine)

  • Tal Iram

    (Stanford University School of Medicine)

  • Liana Bonanno

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Lulin Li

    (Stanford University School of Medicine)

  • Davis P. Lee

    (Stanford University School of Medicine)

  • David W. Morgens

    (Stanford University School of Medicine)

  • Andrew C. Yang

    (Stanford University School of Medicine
    Stanford University)

  • Steven R. Shuken

    (Stanford University School of Medicine
    Stanford University)

  • David Gate

    (Stanford University School of Medicine)

  • Madeleine Scott

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Purvesh Khatri

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Jian Luo

    (Stanford University School of Medicine
    Veterans Administration Palo Alto Healthcare System)

  • Carolyn R. Bertozzi

    (Stanford University School of Medicine
    Stanford University
    Stanford University
    Stanford University)

  • Michael C. Bassik

    (Stanford University
    Stanford University School of Medicine)

  • Tony Wyss-Coray

    (Stanford University School of Medicine
    Stanford University
    Veterans Administration Palo Alto Healthcare System
    Stanford University School of Medicine)

Abstract

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

Suggested Citation

  • John V. Pluvinage & Michael S. Haney & Benjamin A. H. Smith & Jerry Sun & Tal Iram & Liana Bonanno & Lulin Li & Davis P. Lee & David W. Morgens & Andrew C. Yang & Steven R. Shuken & David Gate & Madel, 2019. "CD22 blockade restores homeostatic microglial phagocytosis in ageing brains," Nature, Nature, vol. 568(7751), pages 187-192, April.
    • Handle: RePEc:nat:nature:v:568:y:2019:i:7751:d:10.1038_s41586-019-1088-4
    DOI: 10.1038/s41586-019-1088-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1088-4
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-019-1088-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Tian Zhou & Yuxin Li & Xiaoyu Li & Fanzhuo Zeng & Yanxia Rao & Yang He & Yafei Wang & Meizhen Liu & Dali Li & Zhen Xu & Xin Zhou & Siling Du & Fugui Niu & Jiyun Peng & Xifan Mei & Sheng-Jian Ji & Yous, 2022. "Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Simone Bido & Sharon Muggeo & Luca Massimino & Matteo Jacopo Marzi & Serena Gea Giannelli & Elena Melacini & Melania Nannoni & Diana Gambarè & Edoardo Bellini & Gabriele Ordazzo & Greta Rossi & Camill, 2021. "Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Juan F. Quintana & Praveena Chandrasegaran & Matthew C. Sinton & Emma M. Briggs & Thomas D. Otto & Rhiannon Heslop & Calum Bentley-Abbot & Colin Loney & Luis de Lecea & Neil A. Mabbott & Annette MacLe, 2022. "Single cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:568:y:2019:i:7751:d:10.1038_s41586-019-1088-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.