APP intracellular domain derived from amyloidogenic β- and γ-secretase cleavage regulates neprilysin expression.
APP intracellular domain derived from amyloidogenic β- and γ-secretase cleavage regulates neprilysin expression.
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DOI：
10.3389/fnagi.2015.00077
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发表时间：
2015
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;Grösgen S;Haupenthal VJ;Blümel T;Hundsdörfer B;Zimmer VC;Mylonas NT;Tanila H;Müller U;Grimm HS;Hartmann T
阿尔茨海默病（Alzheimer's disease，AD）的特征是β-淀粉样蛋白（Amyloid-β，Aβ）的积聚，A β是由β -和γ-分泌酶对淀粉样前体蛋白（amyloid precursor protein，APP）进行连续的蛋白水解加工而释放的。Aβ肽可以聚集，导致毒性Aβ寡聚体和淀粉样斑块形成。Aβ蓄积不仅依赖于从头合成，还依赖于Aβ降解。脑啡肽酶（NEP）是参与Aβ降解的主要酶之一。在这里，我们调查的NEP调节的分子机制，这是到目前为止有争议的讨论是受APP加工本身。我们发现，NEP的表达是高度依赖于APP胞内结构域（AICD），APP处理释放。缺乏APP加工的小鼠胚胎成纤维细胞，无论是由于缺乏γ-分泌酶复合物[早老素（PS）1/2]的催化活性亚基，还是由于缺乏APP和APP样蛋白2（APLP 2），都显示出NEP表达、活性和蛋白水平降低。通过利用缺乏功能性AICD结构域（APPΔ CT 15）或在编码PS1的基因中表达突变的细胞获得了类似的结果。AICD补充或用AICD编码质粒再转染可以挽救NEP的下调，进一步加强AICD和转录NEP调节之间的联系，其中Fe 65作为重要的衔接蛋白。特别是淀粉样蛋白生成途径产生的AICD似乎更参与NEP表达的调节。在6个转基因AD小鼠模型（APP和APLP 2单敲除、APP/APLP 2双敲除、APP-瑞典人、APP-瑞典人/PS1Δ外显子9和APPΔ CT 15）中，体内NEP基因表达的分析证实了在细胞培养中获得的结果。总之，在本研究中，我们清楚地证明了体外和体内Aβ降解酶NEP的AICD依赖性调节，并阐明了可能有利于开发治疗AD的新治疗策略的潜在机制。
Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the treatment of AD.
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影响因子：
82.9
作者：
Citron, M;Westaway, D;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
5.8
作者：
Grimm, M. O. W.;Stahlmann, C. P.;Hartmann, T.
通讯作者：
Hartmann, T.
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
4.8
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
2.9
作者：
Akiyama, H;Kondo, H;McGeer, PL
通讯作者：
McGeer, PL