Endothelin Converting Enzymes & Amyloid beta Catabolism

描述（申请人提供）：大脑中β -淀粉样蛋白（Abeta）的异常积累被认为在阿尔茨海默病的病因和发病机制中起关键作用。因此，阿尔茨海默病研究的一个主要焦点是阐明产生β的机制。然而，与任何肽一样，β积累的程度不仅取决于它的产生，而且取决于它的去除。在细胞和体外模型中，我们已经将内皮素转换酶-1 （ECE-1）描述为一种β -降解酶，它似乎在细胞内起作用，从而限制了可用于分泌的β -的量。为了确定这种活性的生理意义，我们分析了缺乏ECE-1和一种密切相关的酶ECE-2的小鼠大脑中的β水平。与同龄的对照组相比，这些动物大脑中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ECE活动限制了大脑中β的积累。在本应用中，我们建议进一步验证这一假设，并确定在小鼠模型中β水平的升高是否会导致沉积或增强沉积。此外，我们建议将我们的分析扩展到人脑。鉴于Abeta在AD发病机制中发挥重要作用的证据，了解那些可以影响Abeta水平的因素，如ECE活性，可能为该疾病提供新的见解，并可能提供新的治疗方法。同样重要的是，ECE抑制剂正被开发为新型抗高血压药物。了解慢性ECE活性降低的影响还有一个额外的好处，那就是它可以揭示使用这些药物可能在正常临床试验中未观察到的重大潜在副作用。

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.