Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain
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
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
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
Publication 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.
Metrics
-
- 4,959
- Page views
-
- 731
- Downloads
-
- 28
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Oxygenation levels are a determinative factor in T cell function. Here, we describe how oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hr of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia-inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
-
- Immunology and Inflammation
With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.