Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons

Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of <i>triggering receptor expressed on myeloid cells-2 (TREM2)</i> are associated with an increased risk of devel...

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Autores principales:	Anna Mallach, Johan Gobom, Charles Arber, Thomas M. Piers, John Hardy, Selina Wray, Henrik Zetterberg, Jennifer Pocock
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	dementia Alzheimer’s disease exosomes microglia proteome intercellular signalling Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e5f7dfff72ee4e26a9361a11d732053f
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spelling	oai:doaj.org-article:e5f7dfff72ee4e26a9361a11d732053f2021-11-25T17:08:15ZDifferential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons10.3390/cells101128662073-4409https://doaj.org/article/e5f7dfff72ee4e26a9361a11d732053f2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2866https://doaj.org/toc/2073-4409Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of <i>triggering receptor expressed on myeloid cells-2 (TREM2)</i> are associated with an increased risk of developing dementia. We investigated the influence of the <i>TREM2</i> Alzheimer’s disease risk variant, R47H<sup>het</sup>, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS<sup>+</sup>) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47H<sup>het</sup> iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common <i>TREM2</i> variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47H<sup>het</sup> <i>TREM2</i> variant may underlie the increased risk of Alzheimer’s disease associated with this variant.Anna MallachJohan GobomCharles ArberThomas M. PiersJohn HardySelina WrayHenrik ZetterbergJennifer PocockMDPI AGarticledementiaAlzheimer’s diseaseexosomesmicrogliaproteomeintercellular signallingBiology (General)QH301-705.5ENCells, Vol 10, Iss 2866, p 2866 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	dementia Alzheimer’s disease exosomes microglia proteome intercellular signalling Biology (General) QH301-705.5
spellingShingle	dementia Alzheimer’s disease exosomes microglia proteome intercellular signalling Biology (General) QH301-705.5 Anna Mallach Johan Gobom Charles Arber Thomas M. Piers John Hardy Selina Wray Henrik Zetterberg Jennifer Pocock Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
description	Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of <i>triggering receptor expressed on myeloid cells-2 (TREM2)</i> are associated with an increased risk of developing dementia. We investigated the influence of the <i>TREM2</i> Alzheimer’s disease risk variant, R47H<sup>het</sup>, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS<sup>+</sup>) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47H<sup>het</sup> iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common <i>TREM2</i> variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47H<sup>het</sup> <i>TREM2</i> variant may underlie the increased risk of Alzheimer’s disease associated with this variant.
format	article
author	Anna Mallach Johan Gobom Charles Arber Thomas M. Piers John Hardy Selina Wray Henrik Zetterberg Jennifer Pocock
author_facet	Anna Mallach Johan Gobom Charles Arber Thomas M. Piers John Hardy Selina Wray Henrik Zetterberg Jennifer Pocock
author_sort	Anna Mallach
title	Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
title_short	Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
title_full	Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
title_fullStr	Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
title_full_unstemmed	Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
title_sort	differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e5f7dfff72ee4e26a9361a11d732053f
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Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons

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