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This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation program and EFPIA.","award":["115976"],"award-info":[{"award-number":["115976"]}]},{"name":"Wallenberg Scholar supported by grants from the Swedish Research Council","award":["2018-02532"],"award-info":[{"award-number":["2018-02532"]}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["681712"],"award-info":[{"award-number":["681712"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement","award":["ALFGBG-720931"],"award-info":[{"award-number":["ALFGBG-720931"]}]},{"name":"Alzheimer Drug Discovery Foundation (ADDF), USA","award":["201809-2016862"],"award-info":[{"award-number":["201809-2016862"]}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUK-SRF2016B-2"],"award-info":[{"award-number":["ARUK-SRF2016B-2"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Health Research University College London Hospitals Biomedical Research Centre","award":["#"],"award-info":[{"award-number":["#"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer\u2019s disease risk variant, R47Hhet, 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+) 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 R47Hhet 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 TREM2 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 R47Hhet\u00a0TREM2 variant may underlie the increased risk of Alzheimer\u2019s disease associated with this variant.<\/jats:p>","DOI":"10.3390\/cells10112866","type":"journal-article","created":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T22:06:16Z","timestamp":1635113176000},"page":"2866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-3429","authenticated-orcid":false,"given":"Anna","family":"Mallach","sequence":"first","affiliation":[{"name":"Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Gobom","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, S-43180 Molndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Molndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-8134","authenticated-orcid":false,"given":"Charles","family":"Arber","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-3417","authenticated-orcid":false,"given":"Thomas M.","family":"Piers","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"},{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-7050","authenticated-orcid":false,"given":"Selina","family":"Wray","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, S-43180 Molndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Molndal, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"},{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5812-9331","authenticated-orcid":false,"given":"Jennifer","family":"Pocock","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/ng.2802","article-title":"Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer\u2019s Disease","volume":"45","author":"Lambert","year":"2013","journal-title":"Nat. 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