β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
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DOI：
10.1126/science.286.5440.735
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发表时间：
1999-10-22
期刊：
影响因子：
56.9
通讯作者：
Citron, M
中科院分区：
文献类型：
--
作者：
Vassar, R;Bennett, BD;Citron, M
淀粉样β肽（Aβ）的大脑沉积是阿尔茨海默病的早期和关键特征。 β 生成依赖于两种未知蛋白酶对淀粉样前体蛋白 (APP) 的蛋白水解切割：β 分泌酶和 γ 分泌酶。这些蛋白酶是主要的治疗靶点。克隆并表征了具有 β-分泌酶所有已知特征的跨膜天冬氨酸蛋白酶。这种被称为 BACE（β 位点 APP 裂解酶）的蛋白酶的过度表达增加了 β-分泌酶裂解产物的量，并且这些产物仅在已知的 β-分泌酶位置处被精确裂解。内源性 BACE 信使 RNA 的反义抑制减少了 β-分泌酶裂解产物的量，并且纯化的 BACE 蛋白裂解的 APP 衍生底物具有与 β-分泌酶相同的序列特异性。最后，BACE 的表达模式和亚细胞定位与 β-分泌酶的预期一致。 BACE 抑制剂的未来开发可能有益于治疗阿尔茨海默病。
Cerebral deposition of amyloid beta peptide (A beta) is an early and critical feature of Alzheimer's disease. A beta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular Localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.