Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease.
Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease.
复制标题
DOI：
10.3389/fnagi.2013.00098
复制
发表时间：
2013-12-23
影响因子：
4.8
通讯作者：
Hartmann T
中科院分区：
文献类型：
--
作者：
Grimm MO;Mett J;Stahlmann CP;Haupenthal VJ;Zimmer VC;Hartmann T
阿尔茨海默病（AD）的特征性标志之一是淀粉样蛋白β（Aβ）的积累，导致斑块形成和毒性寡聚Aβ复合物。除了由淀粉样前体蛋白（APP）的淀粉样蛋白形成过程引起的Aβ从头合成外，Aβ水平还高度依赖于Aβ降解。几种酶被描述为切割Aβ。在这篇综述中，我们专注于最突出的Aβ降解酶之一，锌金属蛋白酶Neprilysin（NEP）。在综述的第一部分中，我们讨论了NEP在Aβ降解中的一般作用，以及在正常衰老和AD进展过程中观察到的酶的变化。体内和细胞培养实验表明，NEP水平降低导致Aβ水平升高，反之亦然。在病理情况下，如AD，据报道，NEP水平和活性降低，并已表明，在NEP基因的某些多态性导致AD的风险增加。相反，增加AD小鼠模型中的NEP活性揭示了一些行为测试的改善。因此，增加NEP可能是治疗或保护AD的一个有趣的潜在靶点，因此了解NEP的调节是必不可少的。有趣的是，研究讨论了APP胞内结构域（AICD），APP加工的切割产物之一，与Notch受体加工具有高度相似性，可能参与NEP的转录调节。然而，AICD调节NEP的机制，这可能有助于开发新的治疗策略，到目前为止有争议的讨论和总结在本综述的第二部分。此外，我们审查的影响，AICD不仅在转录调控的NEP，但也进一步的基因。
One of the characteristic hallmarks of Alzheimer’s disease (AD) is an accumulation of amyloid β (Aβ) leading to plaque formation and toxic oligomeric Aβ complexes. Besides the de novo synthesis of Aβ caused by amyloidogenic processing of the amyloid precursor protein (APP), Aβ levels are also highly dependent on Aβ degradation. Several enzymes are described to cleave Aβ. In this review we focus on one of the most prominent Aβ degrading enzymes, the zinc-metalloprotease Neprilysin (NEP). In the first part of the review we discuss beside the general role of NEP in Aβ degradation the alterations of the enzyme observed during normal aging and the progression of AD. In vivo and cell culture experiments reveal that a decreased NEP level results in an increased Aβ level and vice versa. In a pathological situation like AD, it has been reported that NEP levels and activity are decreased and it has been suggested that certain polymorphisms in the NEP gene result in an increased risk for AD. Conversely, increasing NEP activity in AD mouse models revealed an improvement in some behavioral tests. Therefore it has been suggested that increasing NEP might be an interesting potential target to treat or to be protective for AD making it indispensable to understand the regulation of NEP. Interestingly, it is discussed that the APP intracellular domain (AICD), one of the cleavage products of APP processing, which has high similarities to Notch receptor processing, might be involved in the transcriptional regulation of NEP. However, the mechanisms of NEP regulation by AICD, which might be helpful to develop new therapeutic strategies, are up to now controversially discussed and summarized in the second part of this review. In addition, we review the impact of AICD not only in the transcriptional regulation of NEP but also of further genes.
登录
查看更多内容
影响因子：
6.1
作者：
Betts, Vicki;Leissring, Malcolm A.;Walsh, Dominic M.
通讯作者：
Walsh, Dominic M.
影响因子：
2.9
作者：
Akiyama, H;Kondo, H;McGeer, PL
通讯作者：
McGeer, PL
影响因子：
7.7
作者：
Belyaev, Nikolai D.;Nalivaeva, Natalia N.;Turner, Anthony J.
通讯作者：
Turner, Anthony J.
影响因子：
4.8
作者：
Ando, K;Iijima, K;Suzuki, T
通讯作者：
Suzuki, T
影响因子：
4.2
作者：
Caccamo, A;Oddo, S;LaFerla, FA
通讯作者：
LaFerla, FA