Related Experiment Video
Updated: Oct 15, 2025
Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles
Anna Mallach1, Johan Gobom2,3, Henrik Zetterberg2,3,4,5,6
1Department of Neuroinflammation, Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK.
Abstract:
Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47Hhet 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 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 triggering receptor expressed on myeloid cells 2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47Hhet 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 R47Hhet derived exosomes. Furthermore unlike common variant-derived exosomes, R47Hhet exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47Hhet-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.
Insights
Genetic variants in TREM2 impact Alzheimer's disease risk. R47H TREM2 microglia secrete altered exosomes, offering potential therapeutic targets for dementia.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Variants in the TREM2 gene, particularly R47H, are associated with increased dementia risk, especially late-onset Alzheimer's disease.
- Microglia, immune cells in the brain, play a role in neurodegenerative diseases, and their function can be influenced by TREM2 variants.
Purpose of the Study:
- To investigate how TREM2 variants affect exosome secretion dynamics and composition in human induced pluripotent stem cells-derived microglia.
- To determine if altered exosome profiles contribute to the increased risk of Alzheimer's disease associated with TREM2 variants.
Main Methods:
- Utilized human induced pluripotent stem cells-derived microglia with common and R47H TREM2 variants.
- Analyzed exosome size, quantity, and protein content under basal and stimulated conditions (LPS, phagocytosis).
- Assessed the protective effects of exosomes on stressed neurons.
Main Results:
- R47H microglia secreted exosomes with altered quantity and composition compared to controls, though size remained unchanged.
- Exosome secretion was modulated by ATP donors and a TREM2 ligand.
- Stimulated R47H exosomes showed differential expression of cytokines, chemokines, APOE, TREM2, CCL22, and IL-1β.
- R47H exosomes contained proteins involved in transcriptional regulation and metabolism and were less protective to stressed neurons.
Conclusions:
- TREM2 variants significantly alter microglial exosome secretion, impacting their content and function.
- These exosome alterations may contribute to Alzheimer's disease pathogenesis.
- Targeting microglial exosome pathways presents a potential therapeutic strategy for Alzheimer's disease.
