Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.
Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.
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发表时间：
1998
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通讯作者：
J. Buxbaum;K. Liu;Y. Luo;J. Slack;K. Stocking;J. Peschon;R. S. Johnson;B. Castner;D. Cerretti;R. Black
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作者：
J. Buxbaum;K. Liu;Y. Luo;J. Slack;K. Stocking;J. Peschon;R. S. Johnson;B. Castner;D. Cerretti;R. Black
在阿尔茨海默病患者大脑中积累的淀粉样蛋白Abeta是通过淀粉样蛋白前体(APP)的蛋白分解而获得的。APP可以在三个位点进行内蛋白降解处理，一个在Abeta结构域的氨基末端(β-裂解)，一个在Abeta结构域的氨基末端(α-裂解)，以及一个在Abeta结构域的羧基末端(伽马-裂解)。负责这些活动的酶还没有被明确地确定。通过基因敲除，我们现在证明了肿瘤坏死因子α转换酶(TACE)是ADAM家族(去整合素和金属蛋白水解酶家族)的成员，在APP的α-裂解调控中起着核心作用。我们的数据表明，在培养细胞中，TACE可能是负责调节大部分α-裂解的α-分泌酶。此外，我们还表明，抑制该酶会影响培养细胞中APP的分泌和Abeta的形成。
The amyloid protein, Abeta, which accumulates in the brains of Alzheimer patients, is derived by proteolysis of the amyloid protein precursor (APP). APP can undergo endoproteolytic processing at three sites, one at the amino terminus of the Abeta domain (beta-cleavage), one within the Abeta domain (alpha-cleavage), and one at the carboxyl terminus of the Abeta domain (gamma-cleavage). The enzymes responsible for these activities have not been unambiguously identified. By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells. Furthermore, we show that inhibiting this enzyme affects both APP secretion and Abeta formation in cultured cells.