Valosin-containing protein is cargo in Amyloid Precursor Protein extracellular vesicles

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer's disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App.