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The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles
Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47H(het) triggering receptor expressed on myeloid cells 2 variant is linked to late-onset Alzheimer’s disease. Using human induced pluripotent stem cells-derived mi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244649/ https://www.ncbi.nlm.nih.gov/pubmed/34704019 http://dx.doi.org/10.1093/braincomms/fcab009 |
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author | Mallach, Anna Gobom, Johan Zetterberg, Henrik Hardy, John Piers, Thomas M Wray, Selina Pocock, Jennifer M |
author_facet | Mallach, Anna Gobom, Johan Zetterberg, Henrik Hardy, John Piers, Thomas M Wray, Selina Pocock, Jennifer M |
author_sort | Mallach, Anna |
collection | PubMed |
description | Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47H(het) triggering receptor expressed on myeloid cells 2 variant is linked to late-onset Alzheimer’s disease. Using human induced pluripotent stem cells-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47H(het) variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine triggering receptor expressed on myeloid cells 2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47H(het) microglia were found to contain cytokines, chemokines, APOE and triggering receptor expressed on myeloid cells 2. Differences were observed in the expression of CCL22, IL-1β and triggering receptor expressed on myeloid cells 2 between common variant and R47H(het) derived exosomes. Furthermore unlike common variant-derived exosomes, R47H(het) exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47H(het)-derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer’s disease and may point to further targets for therapeutic intervention. |
format | Online Article Text |
id | pubmed-8244649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-82446492022-01-05 The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles Mallach, Anna Gobom, Johan Zetterberg, Henrik Hardy, John Piers, Thomas M Wray, Selina Pocock, Jennifer M Brain Commun Original Article Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47H(het) triggering receptor expressed on myeloid cells 2 variant is linked to late-onset Alzheimer’s disease. Using human induced pluripotent stem cells-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47H(het) variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine triggering receptor expressed on myeloid cells 2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47H(het) microglia were found to contain cytokines, chemokines, APOE and triggering receptor expressed on myeloid cells 2. Differences were observed in the expression of CCL22, IL-1β and triggering receptor expressed on myeloid cells 2 between common variant and R47H(het) derived exosomes. Furthermore unlike common variant-derived exosomes, R47H(het) exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47H(het)-derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer’s disease and may point to further targets for therapeutic intervention. Oxford University Press 2021-02-03 /pmc/articles/PMC8244649/ /pubmed/34704019 http://dx.doi.org/10.1093/braincomms/fcab009 Text en © Crown copyright 2021. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Mallach, Anna Gobom, Johan Zetterberg, Henrik Hardy, John Piers, Thomas M Wray, Selina Pocock, Jennifer M The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title | The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title_full | The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title_fullStr | The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title_full_unstemmed | The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title_short | The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
title_sort | influence of the r47h triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244649/ https://www.ncbi.nlm.nih.gov/pubmed/34704019 http://dx.doi.org/10.1093/braincomms/fcab009 |
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