Iron overload inhibits neuronal extracellular vesicles secretion via SNARE dysfunction

Iron deposition in the brain is observed in several neurodegenerative diseases and aging. Extracellular vesicles (EVs), including exosomes, are critical mediators of intercellular communication. Neuron-derived EVs are recently recognized as promising biomarkers in the plasma for neurological disorders. However, it remains unclear whether and how neuronal iron overload affects EVs (exosomes) secretion. In this study, we used L1 cell adhesion molecule (L1CAM) to label neuron-derived EVs and observed a significant reduction in L1CAM-positive vesicle concentration in the plasma of mice with brain iron deposition. Iron-reduced EVs secretion was also observed in PC12 cells with ferric ammonium citrate treatment. We then reported the inhibition of iron overload on exosomes secretion was independent of cell proliferation, exosomal trafficking pathway and lysosomal degradation pathway, however, probably via disrupting SNARE complex function. Finally, we observed that neuron-derived EVs are more abundant in the plasma of mice during ageing. Our results indicate that iron overload inhibits neuronal EVs secretion both in vivo and in vitro, potentially through dysfunction of the SNARE complex.