Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.
J Neurochem. 2010 Feb;112(4):1045-53. doi: 10.1111/j.1471-4159.2009.06528.x. Epub 2009 Dec 4.
beta-Secretase is the rate limiting enzymatic activity in the production of the amyloid-beta peptide (Abeta) and is thought to be involved in Alzheimer's disease (AD) pathogenesis. Although BACE1 (beta-site APP Cleaving Enzyme 1, EC 3.4.23.46) has received significant attention, the related BACE2 (EC 3.4.23.45) has not. Though BACE2 is also expressed in the brain, its potential role in AD has not been resolved. In this study, we compared the activities of both BACE1 and BACE2, which were isolated from the same samples of frontal cortex from both AD-affected individuals and age-matched controls. BACE1 activity showed a significant positive correlation with the amount of extractable Abeta, and BACE1 protein and activity were significantly increased in AD cases. Unexpectedly, there were substantial total amounts of BACE2 protein and enzymatic activity in the human brain. BACE2 activity did not change significantly in the AD brain, and was not related to Abeta concentration. These data indicate that BACE1 likely accounts for most of the Abeta produced in the human brain, and that BACE2 activity is not a likely contributor. However, as both forms of BACE compete for the same substrate pool, even small changes in BACE2 activity could have consequences for human disease.
β-分泌酶是淀粉样肽（Abeta）产生过程中的限速酶活性，被认为与阿尔茨海默病（AD）的发病机制有关。尽管 BACE1（β-位点 APP 裂解酶 1，EC 3.4.23.46）受到了广泛关注，但相关的 BACE2（EC 3.4.23.45）却没有。尽管 BACE2 也在大脑中表达，但它在 AD 中的潜在作用尚未得到解决。在这项研究中，我们比较了从 AD 患者和年龄匹配的对照组相同额皮质样本中分离出的 BACE1 和 BACE2 的活性。BACE1 活性与可提取 Abeta 的量呈显著正相关，AD 病例中的 BACE1 蛋白和活性显著增加。出乎意料的是，人脑中有大量的 BACE2 蛋白和酶活性。AD 大脑中的 BACE2 活性没有明显变化，与 Abeta 浓度无关。这些数据表明，BACE1 可能负责大脑中产生的大部分 Abeta，而 BACE2 活性不太可能是其来源。然而，由于两种形式的 BACE 都竞争相同的底物池，即使 BACE2 活性发生微小变化，也可能对人类疾病产生影响。
