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J. Biol. Chem., Vol. 283, Issue 21, 14826-14834, May 23, 2008

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Sortilin-related Receptor with A-type Repeats (SORLA) Affects the Amyloid Precursor Protein-dependent Stimulation of ERK Signaling and Adult Neurogenesis^*

Michael Rohe¹, Anne-Sophie Carlo¹, Henning Breyhan, Anje Sporbert², Daniel Militz, Vanessa Schmidt, Christian Wozny^¶, Anja Harmeier^||, Bettina Erdmann, Kelly R. Bales^**, Susanne Wolf, Gerd Kempermann, Steven M. Paul^**, Dietmar Schmitz^¶, Thomas A. Bayer, Thomas E. Willnow³, and Olav M. Andersen

From the Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany, the ^||Institute for Biochemistry, Free University, 14195 Berlin, Germany, the ^¶Neuroscience Research Centre, Charité, 10117 Berlin, Germany, the Department of Psychiatry, University Medical Center, 37075 Goettingen, Germany, and ^**Lilly Research Laboratories, Indianapolis, Indiana 46285

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid β-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.

Received for publication, December 31, 2007 , and in revised form, February 28, 2008.

^* This work was supported in part by grants from the DFG 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-S3.

¹ These authors contributed equally to this work.

² Supported by a fellowship from the Helmholtz Association.

³ To whom correspondence should be addressed: Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Str. 10, D-13125 Berlin, Germany. Tel.: 49-30-9406-2569; Fax: 49-30-9406-3382; E-mail: willnow{at}mdc-berlin.de.

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