Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at synapses

Neuronal extracellular vesicles (EVs) play critical roles in intercellular communication and in propagation of pathogenic proteins in neurological disease. However, little is known about how cargoes are selectively packaged into neuronal EVs. Here, we examined the intracellular traffic and release of the EV cargoes Amyloid Precursor Protein (APP) and Synaptotagmin-4 (Syt4) at presynaptic nerve terminals of motor neurons. We found that loss of the endosomal retromer complex leads to increased EV cargo levels both presynaptically and in EVs, and that this function is separable from previously identified roles of neuronal retromer. Conversely, EV cargo levels are reduced in mutants, and EV cargo sorting depends on a balance between Rab11-mediated recycling and retromer-dependent removal from the EV pathway. Rab11 and retromer have previously been implicated in Alzheimer’s Disease, suggesting that these competing pathways may serve as therapeutic targets for limiting accumulation and release of toxic EV cargoes.