The β-secretase, BACE -: A prime drug target for Alzheimer's disease

被引:164
作者
Vassar, R [1 ]
机构
[1] Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA
关键词
beta-secretase; BACE; Alzheimer's disease; A beta peptide; beta-amyloid; APP processing;
D O I
10.1385/JMN:17:2:157
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Evidence suggests that the beta -amyloid peptide (A beta) is central to the pathophysiology of Alzheimer's disease (AD). Amyloid plaques, primarily composed of A beta, progressively develop in the brains of AD patients, and mutations in three genes (A PP, PS1, and PS2) cause early onset familial AD (FAD) by directly increasing synthesis of the toxic, plaque-promoting AP42 peptide. Given the strong association between A beta and AD, therapeutic strategies to lower the concentration of A beta in the brain should prove beneficial for the treatment of AD. One such strategy would involve inhibiting the enzymes that generate A beta. A beta is a product of catabolism of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called beta- and gamma -secretase, mediate the endoproteolysis of APP to liberate the A beta 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 identity of 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 together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the beta -secretase, and as the key rate-limiting enzyme that initiates the formation of A beta, BACE1 is an attractive drug target for AD. Here, I review the identification and initial characterization of BACE1 and BACE2, and summarize our current understanding of BACE1 post-translational processing and intracellular trafficking. In addition, I discuss recent studies of BACE1 knockout mice and the BACE1 X-ray structure, and relate implications for BACE1 drug development.
引用
收藏
页码:157 / 170
页数:14
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