Vassar Robert
Northwestern University Medical School, Department of Cell and Molecular Biology, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Adv Drug Deliv Rev. 2002 Dec 7;54(12):1589-602. doi: 10.1016/s0169-409x(02)00157-6.
Evidence suggests that the beta-amyloid peptide (Abeta) is central to the pathophysiology of Alzheimer's Disease (AD). Amyloid plaques, primarily composed of Abeta, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by increasing synthesis of the toxic Abeta42 peptide. Given the strong association between Abeta and AD, therapeutic strategies to lower the concentration of Abeta in the brain should prove beneficial for the treatment of AD. Abeta is a proteolytic product of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called beta- and gamma-secretase, cleave APP to generate the Abeta peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the gamma-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the beta-secretase has been shown to be the novel transmembrane aspartic protease, beta-site APP Cleaving Enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and the two BACE enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the beta-secretase, and as the key enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes our current understanding of BACE1 post-translational processing and intracellular trafficking. Finally, recent studies of BACE1 knockout mice, the BACE1 X-ray structure, and implications for BACE1 drug development will be discussed.
有证据表明，β-淀粉样肽（Aβ）在阿尔茨海默病（AD）的病理生理过程中起核心作用。主要由Aβ组成的淀粉样斑块在AD患者大脑中逐渐形成，三个基因（APP、PS1和PS2）的突变通过增加毒性Aβ42肽的合成导致早发性家族性AD（FAD）。鉴于Aβ与AD之间的紧密联系，降低大脑中Aβ浓度的治疗策略应被证明对AD治疗有益。Aβ是大型I型膜蛋白淀粉样前体蛋白（APP）的蛋白水解产物。两种蛋白酶，即β-分泌酶和γ-分泌酶，切割APP以产生Aβ肽。十多年来，这些蛋白酶的分子身份一直未知。最近，γ-分泌酶已初步被确定为早老素蛋白PS1和PS2，而β-分泌酶已被证明是新型跨膜天冬氨酸蛋白酶β-位点APP切割酶1（BACE1；也称为Asp2和膜内天冬氨酸蛋白酶2）。还鉴定出了与BACE1同源的新型蛋白酶BACE2，这两种BACE酶定义了一个新的跨膜天冬氨酸蛋白酶家族。BACE1具有β-分泌酶的所有特性，作为启动Aβ形成的关键酶，BACE1是AD有吸引力的药物靶点。本文综述了BACE1和BACE2的鉴定及初步特性，并总结了我们目前对BACE1翻译后加工和细胞内运输的理解。最后，将讨论最近关于BACE1基因敲除小鼠、BACE1的X射线结构及其对BACE1药物开发的意义的研究。
