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J. Biol. Chem., Vol. 279, Issue 24, 25333-25338, June 11, 2004

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Presenilin 1 Stabilizes the C-terminal Fragment of the Amyloid Precursor Protein Independently of -Secretase Activity^*

Didier Pitsi and Jean-Noël Octave

From the Laboratoire de Pharmacologie Expérimentale, Université Catholique de Louvain, 1200 Brussels, Belgium

The cleavage of the transmembrane amyloid precursor protein (APP) by -secretase leaves the C-terminal fragment of APP, C99, anchored in the plasma membrane. C99 is subsequently processed by -secretase, an unusual aspartyl protease activity largely dependent on presenilin (PS), generating the amyloid -peptide (A) that accumulates in the brain of patients with Alzheimer's disease. It has been suggested that PS proteins are the catalytic core of this proteolytic activity, but a number of other proteins mandatory for -secretase cleavage have also been discovered. The exact role of PS in the -secretase activity remains a matter of debate, because cells devoid of PS still produce some forms of A. Here, we used insect cells expressing C99 to demonstrate that the expression of presenilin 1 (PS1), which binds C99, not only increases the production of A by these cells but also increases the intracellular levels of C99 to the same extent. Using pulse-chase experiments, we established that this results from an increased half-life of C99 in cells expressing PS1. In Chinese hamster ovary cells producing C99 from full-length human APP, similar results were observed. Finally, we show that a functional inhibitor of -secretase does not alter the ability of PS1 to increase the intracellular levels of C99. This finding suggests that the binding of PS1 to C99 does not necessarily lead to its immediate cleavage by -secretase, which could be a spatio-temporally regulated or an induced event, and provides biochemical evidence for the existence of a substrate-docking site on PS1.

Received for publication, November 20, 2003 , and in revised form, April 14, 2004.

^* This work was supported by the Belgian Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture, the Patrimoine de la Faculté deMédecine de l'UCL, the Communauté Française de Belgique, Actions de Recherche Concertées, the Belgian Fonds de Recherche Scientifique Médicale, and the Queen Elisabeth Medical Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Université Catholique de Louvain, Laboratoire de Pharmacologie Expérimentale, UCL 54.10, 54 Ave. Hippocrate, 1200 Bruxelles, Belgium. Tel.: 32-2-7649341; Fax: 32-2-7645460; E-mail: octave{at}nchm.ucl.ac.be.

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