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Anna Mallach: The influence of the R47H TREM2 variant on microglial exosome profiles
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are linked with an increased risk of dementia, in particular the R47Hhet 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 R47Hhet 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 R47Hhet 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 R47Hhet derived exosomes.