Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain
- Biogen, United States
- Harvard Medical School, United States
- Third Rock Ventures, United States
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.
Data availability
Data are available via ProteomeXchange with identifier PXD017505.Submission details: Project Name: Autofluorescence positive and negative microglia constitute novel subsets found in healthy brain. Project accession: PXD017505
Article and author information
Author details
Jeremy Carlos Burns
Michael Mingueneau
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.
Reviewing Editor
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
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).
Version history
- Received: April 21, 2020
- Accepted: June 21, 2020
- Accepted Manuscript published: June 24, 2020 (version 1)
- Version of Record published: July 17, 2020 (version 2)
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.
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Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain
eLife 9:e57495.
https://doi.org/10.7554/eLife.57495
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