Abstract
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’s 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 TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.
Highlights
Recent studies have identified late-onset Alzheimer’s disease (LO-AD) risk genes associated with microglia, the immune cells of the brain [1,2,3,4]
We have recently shown that the R47Hhet triggering receptor expressed on myeloid cells-2 (TREM2) variant decreased the secretion of exosomes from patient-derived induced pluripotent stem cell-derived microglia [21]
We reported the top 200 most abundant and significantly changed exosomal proteins secreted from iPS-derived microglia (iPS-Mg) [21]; we did not investigate the subtle changes induced by the R47Hhet TREM2 variant and the effects of different iPS-Mg stimuli on the exosomal proteome
Summary
Recent studies have identified late-onset Alzheimer’s disease (LO-AD) risk genes associated with microglia, the immune cells of the brain [1,2,3,4]. One of these genes encodes the triggering receptor expressed on myeloid cells-2 (TREM2) protein, which is expressed on microglia in the central nervous system and senses lipids, such as phospholipids, in the extracellular environment [5,6,7]. One key microglial function is the secretion of a range of factors, including exosomes [13,14]. Exosomal content has been shown to change depending on the signals microglia receive [14]
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