Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention.
Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention.
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DOI：
10.1042/bst20051101
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发表时间：
2005
影响因子：
3.9
通讯作者：
E. Eckman;C. Eckman
中科院分区：
文献类型：
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作者：
E. Eckman;C. Eckman
Abeta（淀粉样β蛋白）肽在大脑中的积累是所有形式AD（阿尔茨海默病）的病理标志，降低Abeta水平可以预防或逆转该疾病小鼠模型中的认知缺陷。Abeta持续产生，其浓度部分取决于几种降解酶的活性，包括NEP（脑啡肽酶）、IDE（胰岛素降解酶）、ECE-1（内皮素转化酶1）和ECE-2，可能还有纤溶酶。由于基因突变或基因表达或蛋白水解活性的年龄或疾病相关改变导致的任何这些酶的活性降低可能会增加AD的风险。相反，这些酶的表达增加可赋予保护作用。通过基因治疗、转录激活或甚至药物激活A β降解酶来增加A β降解代表了目前正在细胞培养和动物模型中评估的治疗AD的新治疗策略。在本文中，我们将审查NEP，IDE，ECE和纤溶酶在确定内源性Abeta浓度的作用，突出最近的结果，这些酶的调节和它们作为治疗靶点的潜力。
The accumulation of Abeta (amyloid beta-protein) peptides in the brain is a pathological hallmark of all forms of AD (Alzheimer's disease) and reducing Abeta levels can prevent or reverse cognitive deficits in mouse models of the disease. Abeta 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 Abeta degradation through gene therapy, transcriptional activation or even pharmacological activation of the Abeta-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 Abeta concentration, highlighting recent results concerning the regulation of these enzymes and their potential as therapeutic targets.