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J. Biol. Chem., Vol. 280, Issue 18, 17777-17785, May 6, 2005

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The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate^*

Christine A. F. von Arnim, Ayae Kinoshita, Ithan D. Peltan, Michelle M. Tangredi, Lauren Herl, Bonny M. Lee, Robert Spoelgen, Tammy T. Hshieh, Sripriya Ranganathan¶, Frances D. Battey¶, Chun-Xiang Liu¶, Brian J. Bacskai, Sanja Sever||, Michael C. Irizarry, Dudley K. Strickland¶, and Bradley T. Hyman**

From the Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, the ^¶Departments of Surgery and Physiology, University of Maryland School of Medicine, Rockville, Maryland 20855, and the ^||Renal Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

BACE is a transmembrane protease with -secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for -secretase, leading to release of amyloid- peptide (A), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.

Received for publication, December 17, 2004 , and in revised form, February 22, 2005.

^* This work was supported by National Institutes of Health Grants AG12406, AG15379, and P50AG05134, DFG (Deutsche Forschungsgemeinschaft) Grants AR 379/1-1 (to C. A. F. v. A.) and HL50784, HL54710 (to D. K. S.), National Institutes of Health Grant EB00768 (to B. J. B.), the American Federation for Aging Research Beeson-Award, and the J. D. French Alzheimer Foundation (to M. C. I). 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Neurology/Alzheimer Unit, 114 16th St. (2009), Charlestown, MA 02129. Tel.: 617-726-2299; Fax: 617-724-1480; E-mail: bhyman{at}partners.org.

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