Neprilysin-2 Is an Important β-Amyloid Degrading Enzyme
Neprilysin-2 Is an Important β-Amyloid Degrading Enzyme
复制标题
DOI：
10.1016/j.ajpath.2010.11.012
复制
发表时间：
2011-01-01
影响因子：
6
通讯作者：
Marr, Robert A.
中科院分区：
文献类型：
--
作者：
Hafez, Daniel;Huang, Jeffrey Y.;Marr, Robert A.
降解淀粉样蛋白-p肽（A β）的蛋白酶在预防阿尔茨海默病（AD）方面很重要，了解这些蛋白酶对于了解AD病理学至关重要。对thiorphan和phosphoramidon抑制敏感的内肽酶尤其重要，因为这些抑制剂在啮齿动物中诱导显著的A β积累（类似于30至50倍）和病理性沉积。A β降解酶脑啡肽酶（NEP）是这些抑制剂的最佳已知靶标。然而，NEP的基因切除仅导致A β的适度增加（类似于1.5至2倍），表明其他硫啡烷/磷酰胺敏感性内肽酶在起作用。特别令人感兴趣的是NEP同系物脑啡肽酶2（NEP 2），其对硫啡烷/磷酰胺敏感并降解A。我们通过使用基因敲除和转基因小鼠研究了NEP 2在体内A β降解中的作用。NEP 2基因缺陷的小鼠显示海马和脑干/间脑中总A β物质显著升高（类似于1.5倍）。在与APP转基因小鼠杂交的NEP 2敲除小鼠中，A β积累的增加更为显著。在NEP/NEP 2双敲除小鼠中，与NEP-/-/NEP 2（+/+）对照相比，A β水平略微增加（类似于1.5至2倍）。用phosphoramidon治疗这些双敲除小鼠导致A β升高，表明还有其他NEP样A β降解内肽酶有助于A β催化。(Am Pathol 2011，178：306-312; DOI：10.1016/j.ajpath.2010.11.012）
Proteases that degrade the amyloid-p peptide (A beta) are important in protecting against Alzheimer's disease (AD), and understanding these proteases is critical to understanding AD pathology. Endopeptidases sensitive to inhibition by thiorphan and phosphoramidon are especially important, because these inhibitors induce dramatic A beta accumulation (similar to 30- to 50-fold) and pathological deposition in rodents. The A beta-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases (similar to 1.5- to 2-fold) in A beta, indicating that other thiorphan/phosphoramidon-sensitive endopeptidases are at work. Of particular interest is the NEP homolog neprilysin 2 (NEP2), which is thiorphan/phosphoramidon-sensitive and degrades A. We investigated the role of NEP2 in A beta degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total A beta species in the hippocampus and brainstem/diencephalon (similar to 1.5-fold). Increases in A beta accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, A beta levels were marginally increased (similar to 1.5- to 2-fold), compared with NEP-/-/NEP2(+/+) controls. Treatment of these double-knockout mice with phosphoramidon resulted in elevations of A beta, suggesting that yet other NEP-like A beta-degrading endopeptidases are contributing to A beta catabolism. (Am Pathol 2011, 178:306-312; DOI: 10.1016/j.ajpath.2010.11.012)