Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes

• Published in: The FASEB journal Vol. 22; no. 5; pp. 1469 - 1478
• Main Authors: Sharples, Robyn A, Vella, Laura J, Nisbet, Rebecca M, Naylor, Ryan, Perez, Keyla, Barnham, Kevin J, Masters, Colin L, Hill, Andrew F
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.05.2008
• Subjects: Alzheimer Disease - physiopathology; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - secretion; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Carbamates - pharmacology; Cattle; CHO Cells; Cricetinae; Cricetulus; Culture Media, Conditioned - pharmacology; Cytoplasmic Vesicles - physiology; Dipeptides - pharmacology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.07-9357com

Alzheimer's disease (AD) is the most common form of dementia and is associated with the deposition of the 39- to 43-amino acid β-amyloid peptide (Aβ) 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 Aβ. In addition, inhibition of γ-secretase results in a significant increase in the amount of α- and β-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.--Sharples, R. A., Vella, L. J., Nisbet, R. M., Naylor, R., Perez, K., Barnham, K. J., Masters, C. L., Hill, A. F. Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes.