In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase.
In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase.
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发表时间：
2005
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通讯作者：
S. Kitazume;K. Nakagawa;R. Oka;Y. Tachida;Kazuko Ogawa;Yi Luo;M. Citron;H. Shitara;C. Taya;H. Yonekawa;J. Paulson;E. Miyoshi;N. Taniguchi;Y. Hashimoto
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作者：
S. Kitazume;K. Nakagawa;R. Oka;Y. Tachida;Kazuko Ogawa;Yi Luo;M. Citron;H. Shitara;C. Taya;H. Yonekawa;J. Paulson;E. Miyoshi;N. Taniguchi;Y. Hashimoto
β - site淀粉样蛋白前体蛋白切割酶1 （BACE1）是一种膜结合的天门氨酸蛋白酶，可切割淀粉样蛋白前体蛋白产生神经毒性肽Abeta，并与触发阿尔茨海默病的发病机制有关。我们之前报道了BACE1切割大鼠β -半乳糖苷α 2,6-唾液转移酶（ST6Gal I）在COS细胞中过表达，并且从细胞分泌的ST6Gal I的NH(2)端（E41形式）为Glu（41）。在这里，我们报道了BACE1基因敲除小鼠的血浆ST6Gal I是对照小鼠的三分之一，这表明BACE1是体内负责切割ST6Gal I的主要蛋白酶。我们还发现bace1转基因小鼠血浆中ST6Gal I水平升高。已知在急性期反应中，肝脏向血浆中分泌ST6Gal I被上调。为了研究BACE1在体内ST6Gal I分泌中的作用，我们分析了肝病理模型Long-Evans Cinnamon （LEC）大鼠肝脏中BACE1 mRNA的水平以及血浆中ST6Gal I的水平。这只大鼠是一种突变体，它在肝脏中自发地积累铜，并导致肝损伤。早在6周龄时，LEC大鼠肝脏和血浆中BACE1产物ST6Gal I蛋白E41形式的BACE1 mRNA同时增加，再次表明BACE1在体内切割ST6Gal I并控制E41形式的分泌。
beta-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a membrane-bound aspartic protease that cleaves amyloid precursor protein to produce a neurotoxic peptide, Abeta, and is implicated in triggering the pathogenesis of Alzheimer disease. We previously reported that BACE1 cleaved rat beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) that was overexpressed in COS cells and that the NH(2) terminus of ST6Gal I secreted from the cells (E41 form) was Glu(41). 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.