Impact of iPSC-derived microglial exosomes on neurons: Role of TREM2 and implication in Alzheimer's Disease

Microglial exosomes are key secretome components that modulate cell-to-cell communication mediating protective or detrimental effects depending on the environmental context upon release. The R47H variant in the microglial triggering receptor expressed on myeloid cells-2 (TREM2) increases the risk for late-onset Alzheimer’s disease (AD) and influences microglia function, contributing to neurodegeneration. Our group has previously shown that the proteome content of exosomes released by microglia harboring the TREM2 R47H mutation differs from that of TREM2 common variant microglial exosomes, suggesting an altered microglia-neuron interaction and neuronal function upon their secretion. To further investigate how R47H variants or TREM2 loss modifies exosome effects on neurons, we assessed further their effects on human iPSC-neurons. We assessed transcriptome and proteome changes in neurons using RNA-seq and proteomic analyses. Our findings reveal that exosomes secreted by R47H variant iPSC-microglia differentially regulate the neuronal transcriptome associated with metabolic pathways and synaptic function and the observed changes in the cell stress-related proteome of neurons further supports this. Additionally, we provide evidence regarding the effects of these exosomes on pre-synaptic and post-synaptic and apoptotic markers expressed by our neuronal model and the influence of TREM2 status on synaptic functioning. Collectively, our data contribute to the characterization of human microglial exosome functions and provide novel insights into how this emerging communication pathway is affected by TREM2 late-onset AD risk variants.