Exploring the neuroprotective potential of astrocyte-derived mitoEVs in an Alzheimer's Disease mouse model

Mitochondria are dynamic organelles essential for neuronal energy supply and their dysfunction is associated with the early stages of neurodegenerative disorders like Alzheimer’s disease. Increasing evidence suggests that astrocytes contribute to neuronal mitochondrial homeostasis by degrading damaged organelles transferred from neurons or by donating functional mitochondrial material. Among the proposed mechanisms, mitochondrial transfer can occur via secretion of extracellular vesicles (EVs). Recently, a new EV subpopulation, named mitovesicles (mitoEVs), has been described. These vesicles possess a double membrane, are enriched in mitochondrial proteins and retain membrane potential, suggesting a possible protective role on metabolism. In this study, we used primary astrocytes and neurons derived from App^NL-G-F mouse brains to investigate how mitoEVs derived from wild-type astrocytes affect this knock-in AD model. We observed that mitoEVs from WT and App^NL-G-F astrocytes share structural features but differ in protein content, suggesting potential functional differences. A safe dosage for neuronal treatment was determined; however, we did not observe any substantial alteration in synaptic ATP levels in treated neurons. Notably, treatment of AD neurons with WT mitoEVs reduced lipid droplets accumulation, whereas App^NL-G-F mitoEVs failed to do so, supporting the hypothesis that vesicle cargo influences its neuroprotective potential. Altogether, these findings suggest that astrocytic mitoEVs may exert neuroprotective effects by restoring lipid homeostasis, shedding new light on the role of EVs in metabolic communication. However, their precise mechanism of action remains to be clarified.