The presence of ubiquitin and ubiquitin conjugates has been detected in patients affected by neurodegenerative diseases such as Alzheimer's disease. We investigated the role of ubiquitin in the degradation of amyloid beta-protein precursor (APP) and its participation in the process of amyloid beta-protein formation. APP was tested as a substrate for ubiquitin-mediated degradation, using both the extracellular and the intracellular forms of APP770, APP751 and APP695. The intracellular APP forms did not show appreciable ubiquitin-mediated degradation. In contrast, the three extracellular forms of APP were degraded in vitro by this proteolytic pathway, with similar degradation rates. Our results suggest a potential regulatory role for the ubiquitin-dependent degradation mechanism in the in vivo APP metabolic pathway.