Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence.
Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence.
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DOI：
10.1038/srep11086
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发表时间：
2015-06-16
影响因子：
4.6
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Chu J;Li JG;Hoffman NE;Stough AM;Madesh M;Praticò D
Aβ的形成直接受γ-分泌酶复合体及其激活剂γ-分泌酶激活蛋白的控制。GSAP是由一个较大的前体蛋白的C末端片段通过caspase-3介导的切割而来的。然而，调控这一过程的机制仍不清楚。在这里，我们提供了体外实验证据，证明5-脂氧合酶(5LO)是GSAP形成的内源性调节因子，而不是其他已知的γ分泌酶调节剂，通过直接和特异性地激活Caspase-3。这些结果通过使用阿尔茨海默病转基因小鼠模型在体内得到证实，在该模型中，5LO水平和活性受到遗传或药物调节。综上所述，我们的发现表明，通过caspase-3的GSAP切割是受调控的，并取决于5LO的可用性，进一步确立了该蛋白作为阿尔茨海默病的一个有吸引力和可行的治疗靶点。
The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer’s disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer’s disease.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Chu, Jin;Giannopoulos, Phillip F.;Ceballos-Diaz, Carolina;Golde, Todd E.;Pratico, Domenico
通讯作者：
Pratico, Domenico
影响因子：
11.2
作者：
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通讯作者：
Pratico, Domenico
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影响因子：
5.1
作者：
Shi, Song-sheng;Yang, Wei-zhong;Chen, Yan
通讯作者：
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影响因子：
3.3
作者：
Stepanichev, MY;Kudryashova, IV;Gulyaeva, NV
通讯作者：
Gulyaeva, NV