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J. Biol. Chem., Vol. 283, Issue 12, 7733-7744, March 21, 2008

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Amyloidogenic Processing but Not Amyloid Precursor Protein (APP) Intracellular C-terminal Domain Production Requires a Precisely Oriented APP Dimer Assembled by Transmembrane GXXXG Motifs^*

Pascal Kienlen-Campard, Bernadette Tasiaux, Joanne Van Hees, Mingli Li, Sandra Huysseune, Takeshi Sato^¶, Jeffrey Z. Fei^||, Saburo Aimoto^¶, Pierre J. Courtoy^**, Steven O. Smith^||, Stefan N. Constantinescu, A Research Associate of the National Fund for Scientific Research, Belgium¹, and Jean-Noël Octave²

From the Center for Neurosciences, Experimental Pharmacology Unit, Christian de Duve Institute and Ludwig Institute for Cancer Research, and ^**Christian de Duve Institute of Cellular Pathology, Cell Unit, Université Catholique de Louvain, B-1200 Brussels, Belgium, ^||Department of Biochemistry and Cell Biology, Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-5115, and ^¶Institute for Protein Research, Osaka University, Osaka 565-0871, Japan

The β-amyloid peptide (Aβ) is the major constituent of the amyloid core of senile plaques found in the brain of patients with Alzheimer disease. Aβ is produced by the sequential cleavage of the amyloid precursor protein (APP) by β- and -secretases. Cleavage of APP by -secretase also generates the APP intracellular C-terminal domain (AICD) peptide, which might be involved in regulation of gene transcription. APP contains three Gly-XXX-Gly (GXXXG) motifs in its juxtamembrane and transmembrane (TM) regions. Such motifs are known to promote dimerization via close apposition of TM sequences. We demonstrate that pairwise replacement of glycines by leucines or isoleucines, but not alanines, in a GXXXG motif led to a drastic reduction of Aβ40 and Aβ42 secretion. β-Cleavage of mutant APP was not inhibited, and reduction of Aβ secretion resulted from inhibition of -cleavage. It was anticipated that decreased -cleavage of mutant APP would result from inhibition of its dimerization. Surprisingly, mutations of the GXXXG motif actually enhanced dimerization of the APP C-terminal fragments, possibly via a different TM -helical interface. Increased dimerization of the TM APP C-terminal domain did not affect AICD production.

Received for publication, August 27, 2007 , and in revised form, January 16, 2008.

^* This work was supported by Action de Recherche Concertée Grant ARC 03/08-299 from the French Community of Belgium (to J.-N. O. and P. J. C.), by Interuniversity Attraction Poles Programme-Belgian State-Belgian Science Policy, the Belgian Fonds de Recherche Scientifique Médicale (to J.-N. O.), the Queen Elisabeth Medical Foundation (to J.-N. O.), National Institutes of Health Grant AG027317 (to S. O. S.), and funds from the De Hovre Foundation, the Fonds Speciaux de Recherche, the Christian de Duve Institute of Cellular Pathology, and the National Fund for Scientific Research, Belgium (to S. N. C.), and a Stichting voor Alzheimer Onderzoek-Fondation pour la Recherche sur la Maladie Alzheimer grant (to P. K.-C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Fig. 1.

¹ To whom correspondence may be addressed: Université Catholique de Louvain, de Duve Institute and Ludwig Institute for Cancer Research, av. Hippocrate 74, B-1200 Brussels, Belgium. E-mail: stefan.constantinescu{at}bru.licr.org. ² To whom correspondence may be addressed: Université Catholique de Louvain, Experimental Pharmacology Unit, FARL/UCL 54 10, av. Hippocrate 54, B-1200 Brussels, Belgium. E-mail: octave{at}nchm.ucl.ac.be.

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