1. Immunology and Inflammation
  2. Neuroscience
Download icon

Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain

  1. Jeremy Carlos Burns
  2. Bunny Cotleur
  3. Dirk M Walther
  4. Bekim Bajrami
  5. Stephen J Rubino
  6. Ru Wei
  7. Nathalie Franchimont
  8. Susan L Cotman
  9. Richard M Ransohoff
  10. Michael Mingueneau  Is a corresponding author
  1. Biogen, United States
  2. Harvard Medical School, United States
  3. Third Rock Ventures, United States
Tools and Resources
  • Cited 0
  • Views 558
  • Annotations
Cite this article as: eLife 2020;9:e57495 doi: 10.7554/eLife.57495

Abstract

To date, microglia subsets in the healthy CNS have not been identified. Utilizing autofluorescence (AF) as a discriminating parameter, we identified two novel microglia subsets in both mice and non-human primates, termed autofluorescence-positive (AF+) and negative (AF-). While their proportion remained constant throughout most adult life, the AF signal linearly and specifically increased in AF+ microglia with age and correlated with a commensurate increase in size and complexity of lysosomal storage bodies, as detected by transmission electron microscopy and LAMP1 levels. Post-depletion repopulation kinetics revealed AF- cells as likely precursors of AF+ microglia. At the molecular level, the proteome of AF+ microglia showed overrepresentation of endolysosomal, autophagic, catabolic, and mTOR-related proteins. Mimicking the effect of advanced aging, genetic disruption of lysosomal function accelerated the accumulation of storage bodies in AF+ cells and led to impaired microglia physiology and cell death, suggestive of a mechanistic convergence between aging and lysosomal storage disorders.

Article and author information

Author details

  1. Jeremy Carlos Burns

    Multiple Sclerosis Research Unit, Biogen, Cambridge, United States
    Competing interests
    Jeremy Carlos Burns, currently a full-time employee of Biogen.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3853-0237
  2. Bunny Cotleur

    Emerging Neurosciences Research Unit, Biogen, Cambridge, United States
    Competing interests
    Bunny Cotleur, currently a full-time employee of Biogen.
  3. Dirk M Walther

    Chemical Biology and Proteomics, Biogen, Cambridge, United States
    Competing interests
    Dirk M Walther, currently a full-time employee of Biogen.
  4. Bekim Bajrami

    Chemical Biology and Proteomics, Biogen, Cambridge, United States
    Competing interests
    Bekim Bajrami, currently a full-time employee of Biogen.
  5. Stephen J Rubino

    Multiple Sclerosis Research Unit, Biogen, Cambridge, United States
    Competing interests
    Stephen J Rubino, currently a full-time employee of Biogen.
  6. Ru Wei

    Chemical Biology and Proteomics, Biogen, Cambridge, United States
    Competing interests
    Ru Wei, currently a full-time employee of Biogen.
  7. Nathalie Franchimont

    Multiple Sclerosis Research Unit, Biogen, Cambridge, United States
    Competing interests
    Nathalie Franchimont, currently a full-time employee of Biogen.
  8. Susan L Cotman

    Center for Genomic Medicine, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  9. Richard M Ransohoff

    Third Rock Ventures, Boston, United States
    Competing interests
    Richard M Ransohoff, currently a full-time employee of Third Rock Ventures.
  10. Michael Mingueneau

    Immunology Research, Biogen, Cambridge, United States
    For correspondence
    michael.mingueneau@biogen.com
    Competing interests
    Michael Mingueneau, currently a full-time employee of Biogen.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3873-7329

Funding

Batten Disease Support and Research Association

  • Susan L Cotman

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

Ethics

Animal experimentation: This study was performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Research animals at Biogen were housed in an AAALAC accredited facility and handled according to an approved institutional animal care and use committee (IACUC) protocol (#756). This study was reviewed and approved by the Massachusetts General Hospital (MGH) Subcommittee of Research Animal Care (SRAC), which serves as the Institutional Animal Care and Use Committee (IACUC) for MGH (Protocol #2008N000013).

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: April 2, 2020
  2. Accepted: June 21, 2020
  3. Accepted Manuscript published: June 24, 2020 (version 1)

Copyright

© 2020, Burns 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.

Metrics

  • 558
    Page views
  • 156
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    Heike Danzer et al.
    Research Article
    1. Cell Biology
    2. Immunology and Inflammation
    Emma J Fenech et al.
    Research Article