Vassar R, Bennett B D, Babu-Khan S, Kahn S, Mendiaz E A, Denis P, Teplow D B, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski M A, Biere A L, Curran E, Burgess T, Louis J C, Collins F, Treanor J, Rogers G, Citron M
Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799, USA.
Science. 1999 Oct 22;286(5440):735-41. doi: 10.1126/science.286.5440.735.
Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta 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.
β淀粉样肽（Aβ）在大脑中的沉积是阿尔茨海默病早期的关键特征。Aβ的产生依赖于淀粉样前体蛋白（APP）被两种未知蛋白酶β-分泌酶和γ-分泌酶进行蛋白水解切割。这些蛋白酶是主要的治疗靶点。一种具有β-分泌酶所有已知特征的跨膜天冬氨酸蛋白酶被克隆并鉴定。这种被称为BACE（β位点APP切割酶）的蛋白酶的过表达增加了β-分泌酶切割产物的量，并且这些产物仅在已知的β-分泌酶切割位点被准确切割。对内源性BACE信使RNA的反义抑制降低了β-分泌酶切割产物的量，并且纯化的BACE蛋白以与β-分泌酶相同的序列特异性切割APP衍生底物。最后，BACE的表达模式和亚细胞定位与β-分泌酶预期的一致。BACE抑制剂的未来开发可能被证明对阿尔茨海默病的治疗有益。
