1. Immunology and Inflammation
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Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer's disease

  1. Xiaoting Wu
  2. Takashi Saito
  3. Takaomi C Saido
  4. Anna M Barron
  5. Christiane Ruedl  Is a corresponding author
  1. Nanyang Technological University, Singapore
  2. Riken Center for Brain Science, Japan
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Cite this article as: eLife 2021;10:e71879 doi: 10.7554/eLife.71879

Abstract

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady-state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer's disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow cells to the pool of foetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor are replenished by, bone marrow (BM)-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady-state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3 and 4 and supplementary figures

Article and author information

Author details

  1. Xiaoting Wu

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0281-8717
  2. Takashi Saito

    Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Takaomi C Saido

    Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna M Barron

    Nanyang Technological University, singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Christiane Ruedl

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    For correspondence
    ruedl@ntu.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5599-6541

Funding

Ministry of Education - Singapore (MOE AcRF Tier 1)

  • Christiane Ruedl

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

Ethics

Animal experimentation: Mice were bred and maintained in a specific pathogen-free animal facility at the Nanyang Technological University (Singapore). All animal studies were carried out according to the recommendations of the National Advisory Committee for Laboratory Animal Research and ARF SBS/NIE 18081, and 19093 protocols were approved by the Institutional Animal Care and Use Committee of the Nanyang Technological University.

Reviewing Editor

  1. Simon Yona, The Hebrew University of Jerusalem, Israel

Publication history

  1. Received: July 2, 2021
  2. Preprint posted: July 5, 2021 (view preprint)
  3. Accepted: October 4, 2021
  4. Accepted Manuscript published: October 5, 2021 (version 1)

Copyright

© 2021, 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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