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J. Cell Biol. 154 (4): 731-740

Copyright © 2001 by the Rockefeller University Press.


Article

The discrepancy between presenilin subcellular localization and {gamma}-secretase processing of amyloid precursor protein

Philippe Cupers1, Mustapha Bentahir1, Katleen Craessaerts1, Isabelle Orlans1, Hugo Vanderstichele3, Paul Saftig2, Bart De Strooper1, and Wim Annaert1

1 Center for Human Genetics, Neuronal Cell Biology Group, Flanders Interuniversity Institute for Biotechnology and Catholic University of Leuven, B-3000 Leuven, Belgium
2 Department of Biochemistry 2, University of Göttingen, D-37073 Göttingen, Germany
3 Innogenetics NV, B-9052 Gent, Belgium

Address correspondence to Wim Annaert and Bart De Strooper, Center for Human Genetics, Neuronal Cell Biology Group, Herestraat 49, B-3000 Leuven, Belgium. Tel.: (32) 16-346-27. Fax: (32) 16-347-181. E-mail: ad{at}med.kuleuven.ac.be

Abstract: We investigated the relationship between PS1 and {gamma}-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent {gamma}-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no {gamma}-secretase processing was observed when holo-APP or APP-C99, a direct substrate for {gamma}-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent {gamma}-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that {gamma}-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the {gamma}-cleavage of APP-C99. In agreement, we found that intracellular {gamma}-secretase processing of APP-C99-KK both at the {gamma}40 and the {gamma}42 site could be restored partially after brefeldin A treatment. Our data confirm the "spatial paradox" and raise several questions regarding the PS1 is {gamma}-secretase hypothesis.

Key Words: presenilin 1; amyloid peptide; {gamma}-secretase; ER retention; APP processing

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