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

doi:10.1083/jcb.200104045

Published online 13 August 2001. doi:10.1083/jcb.200104045

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© The Rockefeller University Press, 0021-9525/2001/8/731 $5.00
The Journal of Cell Biology, Volume 154, Number 4, August 20, 2001 731-740

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

We investigated the relationship between PS1 and ${gamma}$ -secretaseprocessing of amyloid precursor protein (APP) in primary culturesof neurons. Increasing the amount of APP at the cell surfaceor towards endosomes did not significantly affect PS1-dependent ${gamma}$ -secretase cleavage, although little PS1 is present in thosesubcellular compartments. In contrast, almost no ${gamma}$ -secretaseprocessing was observed when holo-APP or APP-C99, a direct substratefor ${gamma}$ -secretase, were specifically retained in the endoplasmicreticulum (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 processedby PS1-dependent ${gamma}$ -secretase. APP-C99 resides in a compartmentthat is negative for ER, intermediate compartment, and Golgimarker proteins. We conclude that ${gamma}$ -secretase cleavage of APP-C99occurs in a specialized subcellular compartment where littleor no PS1 is detected. This suggests that at least one otherfactor than PS1, located downstream of the ER, is required forthe ${gamma}$ -cleavage of APP-C99. In agreement, we found that intracellular ${gamma}$ -secretase processing of APP-C99-KK both at the ${gamma}$ 40 and the ${gamma}$ 42site could be restored partially after brefeldin A treatment.Our data confirm the "spatial paradox" and raise several questionsregarding the PS1 is ${gamma}$ -secretase hypothesis.

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

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