Cellular Mechanisms for the Release of Exosomes Containing the Amyloid Precursor Protein

The Amyloid Precursor Protein (APP) is a transmembrane protein whose cleavage results in the toxic Aβ fragment identified as the major constituent in the amyloid plaques of Alzheimer’s Disease. Recent evidence has shown that fragments of APP including its intracellular domain are secreted into the extracellular space, possibly via the formation and release of extracellular vesicles called exosomes, which are derived from endosomes. In the Drosophila model, we have manipulated specific components of the membrane trafficking machinery predicted to be involved in APP traffic, and measured their effects on in vivo APPeGFP exosome secretion using fluorescence quantification. We targeted the Vps35, Snx1, and Snx3 components of the endosomal sorting complex called Retromer (which is implicated in Alzheimer’s Disease), and the GTPase Rab11 which has been implicated in exocytosis. Our results indicate that Rab11 and the Snx1 are required for exosome release while Snx3 and Vps35, perhaps working together through the Retromer complex, inhibit the formation of APPeGFP containing exosomes. These findings may provide important distinctions for how specific endo/exosomal traffickin