title: Alzheimer's disease beta-amyloid peptides are released in association with exosomes.
abstract: Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of beta-amyloid (Abeta) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The Abeta peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. The endocytic system has been implicated in the cleavages leading to the formation of Abeta. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated Abeta is released into the extracellular milieu are not clear. Here, we show that beta-cleavage occurs in early endosomes followed by routing of Abeta to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of Abeta peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
authors.forename: Masanori
authors.initials: M
authors.lastname: Honsho
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Zahn
authors.forename: Patrick
authors.initials: P
authors.lastname: Keller
authors.forename: Kathrin D
authors.initials: KD
authors.lastname: Geiger
authors.forename: Paul
authors.initials: P
authors.lastname: Verkade
authors.forename: Kai
authors.initials: K
authors.lastname: Simons
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004705:Endocytosis; D005095:Exoribonucleases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides; D005095:Exoribonucleases