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J. Biol. Chem., Vol. 279, Issue 12, 11984-11991, March 19, 2004

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Modulation of Amyloid Precursor Protein Cleavage by Cellular Sphingolipids^*

Naoya Sawamura, Mihee Ko, Wenxin Yu, Kun Zou, Kentaro Hanada¶, Toshiharu Suzuki||, Jian-Sheng Gong**, Katsuhiko Yanagisawa, and Makoto Michikawa

From the Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan, the Japan Society for the Promotion of Science, Tokyo 102-8471, Japan, the ^¶Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan, the ^||Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan, and the ^**Organization of Pharmaceutical Safety and Research of Japan, Tokyo 100-0013, Japan

Lipid rafts and their component, cholesterol, modulate the processing of -amyloid precursor protein (APP). However, the role of sphingolipids, another major component of lipid rafts, in APP processing remains undetermined. Here we report the effect of sphingolipid deficiency on APP processing in Chinese hamster ovary cells treated with a specific inhibitor of serine palmitoyltransferase, which catalyzes the first step of sphingolipid biosynthesis, and in a mutant LY-B strain defective in the LCB1 subunit of serine palmitoyltransferase. We found that in sphingolipid-deficient cells, the secretion of soluble APP (sAPP) and the generation of C-terminal fragment cleaved at -site dramatically increased, whereas -cleavage activity remained unchanged, and the -cleavage activity decreased without alteration of the total APP level. The secretion of amyloid -protein 42 increased in sphingolipid-deficient cells, whereas that of amyloid -protein 40 did not. All of these alterations were restored in sphingolipid-deficient cells by adding exogenous sphingosine and in LY-B cells by transfection with cLCB1. Sphingolipid deficiency increased MAPK/ERK activity and a specific inhibitor of MAPK kinase, PD98059, restored sAPP level, indicating that sphingolipid deficiency enhances sAPP secretion via activation of MAPK/ERK pathway. These results suggest that not only the cellular level of cholesterol but also that of sphingolipids may be involved in the pathological process of Alzheimer's disease by modulating APP cleavage.

Received for publication, September 4, 2003 , and in revised form, January 8, 2004.

^* This work was supported by Research Grant for Longevity Sciences and Brain Science Research H14-Cyoju-010 from the Ministry of Health and Welfare, Japan, and by funds from the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan. 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.

To whom correspondence should be addressed. Tel.: 81-562-46-2311; Fax: 81-562-44-6594; E-mail: michi{at}nils.go.jp.

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