Aβ-degrading enzymes:: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention
Aβ-degrading enzymes:: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention
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DOI：
10.1042/bst0331101
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发表时间：
2005-11-01
影响因子：
3.9
通讯作者：
Eckman, CB
中科院分区：
文献类型：
--
作者：
Eckman, EA;Eckman, CB
β - 淀粉样蛋白（Aβ）肽在大脑中的积聚是所有形式的阿尔茨海默病（AD）的病理特征，降低Aβ水平可以预防或逆转该疾病小鼠模型中的认知缺陷。Aβ持续产生，其浓度部分由几种降解酶的活性决定，包括脑啡肽酶（NEP）、胰岛素降解酶（IDE）、内皮素转化酶1（ECE - 1）和内皮素转化酶2（ECE - 2），可能还有纤溶酶。由于基因突变，或者基因表达或蛋白水解活性因年龄或疾病相关的改变而导致这些酶中的任何一种活性降低，都可能增加患AD的风险。相反，这些酶表达增加可能具有保护作用。通过基因治疗、转录激活甚至药物激活Aβ降解酶来增加Aβ降解，代表了一种治疗AD的新治疗策略，目前正在细胞培养和动物模型中进行评估。在本文中，我们将综述NEP、IDE、ECE和纤溶酶在决定内源性Aβ浓度中的作用，重点介绍有关这些酶的调节及其作为治疗靶点的潜力的最新研究结果。
The accumulation of A beta (amyloid beta-protein) peptides in the brain is a pathological hallmark of all forms of AD (Alzheimer's disease) and reducing A beta levels can prevent or reverse cognitive deficits in mouse models of the disease. A beta is produced continuously and its concentration is determined in part by the activities of several degradative enzymes, including NEP (neprilysin), IDE (insulin-degrading enzyme), ECE-1 (endothelin-converting enzyme 1) and ECE-2, and probably plasmin. Decreased activity of any of these enzymes due to genetic mutation, or age- or disease-related alterations in gene expression or proteolytic activity, may increase the risk for AD. Conversely, increased expression of these enzymes may confer a protective effect. Increasing A beta degradation through gene therapy, transcriptional activation or even pharmacological activation of the A beta-degrading enzymes represents a novel therapeutic strategy for the treatment of AD that is currently being evaluated in cell-culture and animal models. in this paper, we will review the roles of NEP, IDE, ECE and plasmin in determining endogenous A beta concentration, highlighting recent results concerning the regulation of these enzymes and their potential as therapeutic targets.