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J. Biol. Chem., Vol. 283, Issue 28, 19489-19498, July 11, 2008

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Evidence That CD147 Modulation of β-Amyloid (Aβ) Levels Is Mediated by Extracellular Degradation of Secreted Aβ^*

Kulandaivelu S. Vetrivel¹, Xulun Zhang¹, Xavier Meckler, Haipeng Cheng, Sungho Lee, Ping Gong, Kryslaine O. Lopes, Ying Chen, Nobuhisa Iwata, Ke-Jie Yin^¶, Jin-Moo Lee^¶, Angèle T. Parent, Takaomi C. Saido, Yue-Ming Li^||, Sangram S. Sisodia², and Gopal Thinakaran³

From the Departments of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois 60637, the Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, the ^¶Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^||Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Cerebral deposition of β-amyloid (Aβ) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein -secretase complex generates Aβ. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of -secretase and that the levels of secreted Aβ inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral -secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Aβ levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Aβ production in an in vitro -secretase assay. Consistent with an extracellular source that modulates Aβ metabolism, synthetic Aβ was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on -site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Aβ levels not by regulating -secretase activity, but by stimulating extracellular degradation of Aβ. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Aβ levels by an indirect mechanism involving MMPs that can degrade extracellular Aβ.

Received for publication, February 7, 2008 , and in revised form, April 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG021495 and AG019070 (to G. T.) and AG026660 (to Y.-M. L.). This work was also supported by Grants-in-aid for Scientific Research on Priority Areas 17025046 and 18023037 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N. I.), by an Alzheimer's Association investigator-initiated research grant (to G. T.) and new investigator research grant (to K. S. V.), and by grants from the American Health Assistance Foundation (to G. T. and S. S. S.). 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.

This article was selected as a Paper of the Week.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: Dept. of Neurobiology, The University of Chicago, Abbott 308, 947 E. 58th Street, Chicago, IL 60637. Tel.: 773-834-9186; Fax: 773-702-2926; E-mail: ssisodia{at}bsd.uchicago.edu. ³ To whom correspondence may be addressed: Dept. of Neurobiology, The University of Chicago, Knapp R212, 924 E. 57th St., Chicago, IL 60637. Tel.: 773-834-3752; Fax: 773-834-3808; E-mail: gopal{at}uchicago.edu.

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