Endothelin Converting Enzymes & Amyloid beta Catabolism

描述（由申请人提供）：β-淀粉样蛋白（Abeta）在脑中的异常积累被认为在阿尔茨海默病的病因学和发病机制中起关键作用。因此，AD研究的一个主要焦点是阐明负责产生Abeta的机制。然而，与任何肽一样，Abeta积累的程度不仅取决于其产生，还取决于其去除。在基于细胞的体外模型中，我们先前已经将内皮素转化酶-1（ECE-1）表征为似乎在细胞内起作用的A β降解酶，从而限制可用于分泌的A 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和密切相关的酶ECE-2的小鼠大脑中的Abeta水平。当与年龄匹配的同窝对照相比时，在这些动物的脑中发现A β 40和A β 42的水平显著增加。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Abeta在大脑中的积累。在本申请中，我们提出进一步检验这一假设，并确定这些Abeta水平的升高是否会导致小鼠模型中的沉积或沉积的增强。此外，我们建议将我们的分析扩展到人脑。鉴于有证据表明Abeta在AD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ECE活性，可能会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抑制剂正在被开发为新型抗高血压药。了解ECE活性长期降低的影响具有额外的优势，即它可能揭示使用这些药物的显著潜在副作用，这些副作用在正常临床试验中可能无法观察到。

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.