Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.
Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.
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人膜金属内肽酶样蛋白可降解 β-淀粉样蛋白 42 和 β-淀粉样蛋白 40。
DOI：
10.1016/j.neuroscience.2008.05.006
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发表时间：
2008
期刊：
影响因子：
3.3
通讯作者：
Marr,RA
中科院分区：
文献类型：
--
作者：
Huang,JY;Bruno,AM;Patel,CA;Huynh,AM;Philibert,KD;Glucksman,MJ;Marr,RA
β-淀粉样蛋白（Aβ）降解内肽酶被认为可以预防阿尔茨海默病（AD），并具有潜在的治疗作用。特别感兴趣的是被thiorphan和phosphoramidon（T/P）阻断的内肽酶，因为这些抑制剂在啮齿动物中快速诱导Aβ沉积。脑啡肽酶（NEP）是T/P最知名的靶点;然而，脑啡肽酶敲除仅导致不足以诱导沉积的适度Aβ增加。因此，T/P靶向的其他内肽酶对Aβ catalysts一定是关键的。另一个候选者是T/P敏感性膜金属内肽酶样蛋白（MMEL），一种脑啡肽酶的同源物。在用两种剪接形式的人cDNA转导的HEK 293 T细胞中测定了人MMEL的β和γ剪接形式的内肽酶性质;这表明hMMEL-β降解Aβ 42和Aβ 40，但hMMEL-γ不降解。在细胞外表面发现hMMEL-β活性，没有显著的分泌活性。hMMEL-γ在细胞外表面不表达。最后，发现hMMEL在α-分泌酶位点附近切割Aβ（产生Aβ1-17和Aβ1-16）。这些数据确立了hMMEL作为Aβ catalysts的介质，并提高了其参与AD病因学和作为干预靶点的可能性。
Beta-amyloid (Aβ) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce Aβ deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Aβ increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Aβ catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of β and γ splice forms of human MMEL were determined in HEK293T cells transduced with the human cDNAs for the two splice forms; this showed degradation of both Aβ42and Aβ40by hMMEL-β but not hMMEL-γ. hMMEL-β activity was found at the extracellular surface with no significant secreted activity. hMMEL-γ was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves Aβ near the α-secretase site (producing Aβ1-17≫Aβ1-16). These data establish hMMEL as a mediator of Aβ catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.