Alzheimer's disease (AD) is the most common form of dementia and is associated 
with the deposition of the 39- to 43-amino acid beta-amyloid peptide (Abeta) in 
the brain. C-terminal fragments (CTFs) of amyloid precursor protein (APP) can 
accumulate in endosomally derived multivesicular bodies (MVBs). These 
intracellular structures contain intraluminal vesicles that are released from 
the cell as exosomes when the MVB fuses with the plasma membrane. Here we have 
investigated the role of exosomes in the processing of APP and show that these 
vesicles contain APP-CTFs, as well as Abeta. In addition, inhibition of 
gamma-secretase results in a significant increase in the amount of alpha- and 
beta-secretase cleavage, further increasing the amount of APP-CTFs contained 
within these exosomes. We identify several key members of the secretase family 
of proteases (BACE, PS1, PS2, and ADAM10) to be localized in exosomes, 
suggesting they may be a previously unidentified site of APP cleavage. These 
results provide further evidence for a novel pathway in which APP fragments are 
released from cells and have implications for the analysis of APP processing and 
diagnostics for Alzheimer's disease.