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J. Biol. Chem., Vol. 280, Issue 9, 8589-8595, March 4, 2005

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In Vivo Cleavage of 2,6-Sialyltransferase by Alzheimer -Secretase^*

Shinobu Kitazume, Kazuhiro Nakagawa, Ritsuko Oka, Yuriko Tachida, Kazuko Ogawa, Yi Luo¶, Martin Citron¶, Hiroshi Shitara||, Choji Taya||, Hiromichi Yonekawa||, James C. Paulson**, Eiji Miyoshi, Naoyuki Taniguchi, and Yasuhiro Hashimoto

From the Glyco-chain Functions Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, CREST (Japan), the Science and Technology Agency, Kawaguchi, Saitama 560-0082, Japan, the ^¶Department of Biological Sciences, Amgen, Thousand Oaks, California 91320, the ^||Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan, ^**The Scripps Research Institute, Department of Molecular Biology, La Jolla, California 92037, and the Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita-shi, Osaka 565-871, Japan

-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a membrane-bound aspartic protease that cleaves amyloid precursor protein to produce a neurotoxic peptide, A, and is implicated in triggering the pathogenesis of Alzheimer disease. We previously reported that BACE1 cleaved rat -galactoside 2,6-sialyltransferase (ST6Gal I) that was overexpressed in COS cells and that the NH₂ terminus of ST6Gal I secreted from the cells (E41 form) was Glu⁴¹. Here we report that BACE1 gene knock-out mice have one third as much plasma ST6Gal I as control mice, indicating that BACE1 is a major protease which is responsible for cleaving ST6Gal I in vivo. We also found that BACE1-transgenic mice have increased level of ST6Gal I in plasma. Secretion of ST6Gal I from the liver into the plasma is known to be up-regulated during the acute-phase response. To investigate the role of BACE1 in ST6Gal I secretion in vivo, we analyzed the levels of BACE1 mRNA in the liver, as well as the plasma levels of ST6Gal I, in a hepatopathological model, i.e. Long-Evans Cinnamon (LEC) rats. This rat is a mutant that spontaneously accumulates copper in the liver and incurs hepatic damage. LEC rats exhibited simultaneous increases in BACE1 mRNA in the liver and in the E41 form of the ST6Gal I protein, the BACE1 product, in plasma as early as 6 weeks of age, again suggesting that BACE1 cleaves ST6Gal I in vivo and controls the secretion of the E41 form.

Received for publication, August 17, 2004

^* This work was supported in part by the Frontier Research System Fund (to Y. H.), the Strategic Research Fund (to Y. H.), and the Industrial Collaboration Fund (to Y. H.) from the RIKEN Institute. This work study was also supported by the Leading Project Fund and by Grants-in-aid for Scientific Research, numbers 15040224 (to S. K.), 15025273 (to S. K.), 15770090 (to S. K.), 15631009 (to Y. H.), and 15025273 (to Y. H.) from the Ministry of Education, Science, Sports, and Culture 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: Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel.: 81-48-467-9613; Fax: 81-48-462-4690; E-mail: yasua{at}postman.riken.go.jp.

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