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

• DOI: 10.1096/fj.07-9357com
• Publication Date: 2008-01-03T01:56:21Z
• Authors: Robyn A. Sharples; Laura J. Vella; Rebecca M. Nisbet; Ryan Naylor; Keyla Perez; Kevin J. Barnham; Colin L. Masters; Andrew F. Hill
• Keywords: Alpha secretase; ADAM10; Protein precursor; Amyloid beta; P3 peptide; Cleavage (geology)

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