The influence of the R47H TREM2 variant on microglial exosome profiles. Issue 1 (3rd February 2021)

• Record Type: Journal Article
• Authors: Mallach, Anna; Gobom, Johan; Zetterberg, Henrik; Hardy, John; Piers, Thomas M; Wray, Selina; Pocock, Jennifer M
• Is Part Of: Brain communications. Volume 3:Issue 1(2021)
• Publication Date: 2021-02-03
• Subjects: Exosomes -- Alzheimer's disease -- microglia -- TREM2; 616
• DOI: 10.1093/braincomms/fcab009
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: Variants in the triggering receptor expressed on myeloid cells 2 ( TREM2) gene are linked with an increased risk of dementia, in particular the R47H het TREM2 variant is linked to late-onset Alzheimer's disease. Using human iPSC-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 TREM2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47H het microglia were found to contain cytokines, chemokines, APOE and TREM2. Differences were observed in the expression of CCL22, IL-1β and TREM2 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.