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Published online 1 July 2002. doi:10.1083/jcb.200110151
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© The Rockefeller University Press, 0021-9525/2002/7/79 $5.00
The Journal of Cell Biology, Volume 158, Number 1, July 8, 2002 79-89

Article

 A novel mechanism for the regulation of amyloid precursor protein metabolism

Qi Chen1, Hideo Kimura2 and David Schubert1

1 Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037
2 National Institute of Neuroscience, Kodaira, Tokyo 187-8551, Japan

Address correspondence to David Schubert, The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 453-4100, ext. 1528. Fax: (858) 535-9062. E-mail: schubert{at}salk.edu

Modifier of cell adhesion protein (MOCA; previously called presenilin [PS] binding protein) is a DOCK180-related molecule, which interacts with PS1 and PS2, is localized to brain areas involved in Alzheimer's disease (AD) pathology, and is lost from the soluble fraction of sporadic Alzheimer's disease (AD) brains. Because PS1 has been associated with {gamma}-secretase activity, MOCA may be involved in the regulation of ß-amyloid precursor protein (APP) processing. Here we show that the expression of MOCA decreases both APP and amyloid ß-peptide secretion and lowers the rate of cell-substratum adhesion. In contrast, MOCA does not lower the secretion of amyloid precursor-like protein (APLP) or several additional type 1 membrane proteins. The phenotypic changes caused by MOCA are due to an acceleration in the rate of intracellular APP degradation. The effect of MOCA expression on the secretion of APP and cellular adhesion is reversed by proteasome inhibitors, suggesting that MOCA directs nascent APP to proteasomes for destruction. It is concluded that MOCA plays a major role in APP metabolism and that the effect of MOCA on APP secretion and cell adhesion is a downstream consequence of MOCA-directed APP catabolism. This is a new mechanism by which the expression of APP is regulated.

Key Words: amyloid precursor protein; proteasome; beta amyloid; secre-tion; MOCA


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