Endothelin Converting Enzymes & Amyloid beta Catabolism

描述(申请人提供)：大脑中β-淀粉样蛋白(Abeta)的异常积聚被认为在阿尔茨海默病的病因和发病机制中发挥关键作用。因此，AD研究的一个主要焦点是阐明Abeta产生的机制。然而，与任何多肽一样，Abeta的积累程度不仅取决于它的产生，还取决于它的去除。在基于细胞和体外的模型中，我们以前已经将内皮素转换酶-1(ECE1)描述为一种似乎在细胞内作用的Abeta降解酶，从而限制了可用于分泌的Abeta的数量。为了确定这种活动的生理学意义，我们分析了ECE1和一种密切相关的酶ECE2缺乏的小鼠大脑中的Abeta水平。与年龄匹配的小鼠对照组相比，这些动物的大脑中Abeta40和Abeta42的水平都显著增加。这些数据为我们的工作假设提供了强有力的支持，即欧洲经委会的活动限制了Aβ在大脑中的积累。在这项应用中，我们建议进一步检验这一假设，并确定Abeta水平的这些升高是否会导致小鼠模型中的沉积或增强沉积。此外，我们还建议将我们的分析扩展到人脑。鉴于有证据表明Abeta在AD的发病机制中起着重要作用，了解那些可以影响Abeta水平的因素，如欧洲经委会的活动，可能会为疾病提供新的见解，并可能提供新的治疗方法。同样重要的是，血管紧张素转换酶抑制剂正在被开发为新型降压药。了解欧洲经委会活动长期减少的影响还有一个额外的好处，那就是它可能揭示使用这些药物的一个重大潜在副作用，这些副作用在正常的临床试验中可能没有观察到。

DESCRIPTION (provided by applicant): The abnormal accumulation of beta-amyloid (Abeta) in the brain is believed to play a pivotal role in the etiology and pathogenesis of Alzheimer's disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity we have analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains these animals when compared to age matched, littermate controls. These data provide strong support for our working hypothesis that ECE activity limits Abeta accumulation in the brain. In this application we propose to further test this hypothesis and to determine whether these elevations in Abeta levels will result in deposition or an enhancement of deposition in mouse models. Additionally we propose to extend our analysis into human brain. Given the evidence that Abeta plays a significant role in AD pathogenesis, understanding those factors that can influence Abeta levels, such as ECE activity, may provide new insights into the disease and could provide novel therapeutic approaches. Equally important, ECE inhibitors are being developed as novel anti-hypertensives. Understanding the effects of chronic reductions in ECE activity has the additional advantage that it may shed light on a significant potential side effect of the use of these drugs that may not be observed in normal clinical trials.