Abstract

Role of Exosomes in the Transport of Amyloid Precursor Protein Fragments Between Neurons

Remy Sadoul, ,

Amyloid beta peptide (A?), the main component of senile plaques of Alzheimer’s disease brains, is produced by cleavage of the C-terminal transmembrane fragments (CTFs) of Amyloid Precursor Protein (APP). An unanswered question is how pathological amyoidogenic peptides spread throughout the brain during the course of the disease. We have shown that cortical neurons secrete exosomes which specifically bind to, and are endocytosed by other neurons. Cortical exosomes, carry endogenous APP and are strikingly enriched in CTFs. Using N2a cells expressing human APP and the tetraspanin CD63, we also found that the two proteins are sorted to different subsets of exosomes. We also found that APP carrying exosomes specifically bind to neurons in contrast to CD63-carrying exosomes, which bind to both neurons and glial cells. Thus, neuroblastoma cells secrete distinct populations of exosomes carrying different cargoes and targeting specific cell types. APP-carrying exosomes can be endocytosed by receiving cells allowing the processing of APP acquired by exosomes to give rise to the APP intracellular domain (AICD). Thus, our results show for the first time that neuronal exosomes may indeed act as vehicles for the intercellular transport of APP and its catabolites.