Alzheimer's disease β-amyloid peptide is increased in mice deficient in endothelin-converting enzyme
Alzheimer's disease β-amyloid peptide is increased in mice deficient in endothelin-converting enzyme
复制标题
DOI：
10.1074/jbc.c200642200
复制
发表时间：
2003-01-24
影响因子：
4.8
通讯作者：
Eckman, CB
中科院分区：
文献类型：
--
作者：
Eckman, EA;Watson, M;Eckman, CB
大脑中β-淀粉样蛋白（Abeta）的异常积累是阿尔茨海默病（AD）的早期且不变的特征，并且被认为在该疾病的病因和发病机制中发挥着关键作用。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，我们之前已将内皮素转换酶-1 (ECE-1) 描述为一种 Abeta 降解酶，它似乎在细胞内起作用，从而限制了可分泌的 Abeta 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。与年龄匹配的同窝对照动物相比，这些动物大脑中 Abeta40 和 Abeta42 的水平显着增加。 ECE缺陷小鼠中Abeta水平的增加为ECE-1和ECE-2在限制Abeta在大脑中积累方面的生理作用提供了第一个直接证据，并且还提供了对体内Abeta清除所涉及的因素的进一步了解。
The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the 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 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 of these animals when compared with age-matched littermate controls. The increase in Abeta levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting Abeta accumulation in the brain and also provides further insight into the factors involved in Abeta clearance in vivo.