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J. Biol. Chem., Vol. 282, Issue 45, 32956-32964, November 9, 2007

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SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1^*

From the Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany

SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid -peptide formation.

Received for publication, June 20, 2007 , and in revised form, September 4, 2007.

^* This work was supported in part by grants from the Deutsche Forschungsgemeinschaft and the Alzheimer Forschung Initiative e.V. (to T. E. W.), and the Lundbeck Foundation, the American Health Assistance Foundation, and the Danish Medical Research Council (to O. M. A.). 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 Figs. S1-S6.

¹ Supported by a fellowship from the Helmholtz Association.

² To whom correspondence should be addressed. Tel.: 49-30-9406-2569; Fax: 49-30-9406-3382; E-mail: willnow{at}mdc-berlin.de.

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