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

ABSTRACT Neuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes Amyloid Precursor Protein (APP) and Synaptotagmin-4 (Syt4) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer, and depends on the ESCPE-1 complex. Conversely, loss of the recycling endosome regulator rab11 leads to reduced EV cargo levels, and suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab11-mediated loading and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s Disease, and suggest that misregulated EV traffic may be an underlying defect.