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J. Biol. Chem., Vol. 281, Issue 11, 7583-7594, March 17, 2006

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Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein^*

Stephanie Neumann, Susanne Schöbel, Sebastian Jäger, Anna Trautwein, Christian Haass, Claus U. Pietrzik, and Stefan F. Lichtenthaler¹

From the Adolf-Butenandt-Institut, Ludwig-Maximilians-University, Schillerstrasse 44, 80336 Munich and the Institute of Physiological Chemistry and Pathobiochemistry, University of Mainz, Duesbergweg 6, 55128 Mainz, Germany

Ectodomain shedding of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer disease amyloid peptide (A). The molecular mechanisms underlying the control of APP shedding remain little understood but are in part dependent on the low density lipoprotein receptor-related protein (LRP), which is involved in APP endocytosis. Here, we show that the APP homolog APLP1 (amyloid precursor-like protein 1) influences APP shedding. In human embryonic kidney 293 cells expression of APLP1 strongly activated APP shedding by -secretase and slightly reduced -secretase cleavage. As revealed by domain deletion analysis, the increase in APP shedding required the NPTY amino acid motif within the cytoplasmic domain of APLP1. This motif is conserved in APP and is essential for the endocytosis of APP and APLP1. Unrelated membrane proteins containing similar endocytic motifs did not affect APP shedding, showing that the increase in APP shedding was specific to APLP1. In LRP-deficient cells APLP1 no longer induced APP shedding, suggesting that in wild-type cells APLP1 interferes with the LRP-dependent endocytosis of APP and there by increases APP -cleavage. In fact, an antibody uptake assay revealed that expression of APLP1 reduced the rate of APP endocytosis. In summary, our study provides a novel mechanism for APP shedding, in which APLP1 affects the endocytosis of APP and makes more APP available for -secretase cleavage.

Received for publication, July 29, 2005 , and in revised form, December 8, 2005.

^* This work was supported by a Boehringer Ingelheim foundation fellowship (to S. N. and S. J.), Deutsche Forschungsgemeinschaft SPP1085/2 and SFB596 Project B12 (to S. F. L.), SPP1085/2 (to C. H.), and Pi379/1-3 (to C. U. P.), European Commission Project NeuroNE (to C. H.), and the Excellence Network Nano Biotechnology and the Fonds der Chemischen Industrie (to S. F. L.). 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.

¹ To whom correspondence should be addressed. Tel.: 49-89-218-075-453; Fax: 49-89-218-075-415; E-mail: Stefan.Lichtenthaler{at}med.uni-muenchen.de.

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