FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo .
FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo .
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DOI：
10.1038/tp.2013.106
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发表时间：
2013-12-03
影响因子：
6.8
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Chu J;Lauretti E;Di Meco A;Praticò D
FLAP（5-脂氧合酶激活蛋白）是广泛分布于中枢神经系统内的蛋白质，其功能是调节5-脂氧合酶的激活。尽管先前的工作表明FLAP的药理学阻断改善了Tg2576的淀粉样表型，但其对tau病理学的贡献仍有待研究。在本文中，我们研究了FLAP药理学抑制对这些小鼠内源性tau代谢的影响。与对照组相比，接受MK-591（一种选择性和特异性FLAP抑制剂）的小鼠大脑中的总tau水平没有变化。相比之下，治疗的动物在特定位点：Ser396; Ser396/Ser404;和Thr 231/Ser 235处具有tau磷酸化的显著降低。这种减少与糖原合成酶激酶-3 β的活性显著降低有关，但与其他激酶无关。此外，MK-591给药小鼠的突触后密度蛋白-95和树突状蛋白微管相关蛋白2显著增加。这些数据确立了FLAP在tau代谢中的新功能作用，并且与其已知的A β调节作用一起，它们表明其药理学抑制可能代表阿尔茨海默病的新治疗机会。
FLAP (5-lipoxygenase-activating protein) is a protein widely distributed within the central nervous system whose function is to regulate the activation of the 5-Lipoxygenase enzyme. Although previous works show that pharmacological blockade of FLAP improve the amyloidotic phenotype of the Tg2576, its contribution to tau pathology remains to be investigated. In the present paper, we studied the effect of FLAP pharmacological inhibition on the metabolism of endogenous tau in these mice. Total tau levels in the brains of mice receiving MK-591, a selective and specific FLAP inhibitor, were not changed when compared with controls. By contrast, treated animals had a significant reduction of tau phosphorylation at specific sites: Ser396; Ser396/Ser404; and Thr 231/Ser 235. This reduction was associated with a significant decrease in the activity of glycogen synthase kinase-3 beta, but not other kinases. In addition, MK-591-treated mice had a significant increase in the post-synaptic density protein-95 and the dendritic protein microtubule-associated protein 2. These data establish a novel functional role for FLAP in the metabolism of tau, and together with its known Aβ modulatory effect they suggest that its pharmacological inhibition could represent a novel therapeutic opportunity for Alzheimer's disease.
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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：
Chu, Jin;Pratico, Domenico
通讯作者：
Pratico, Domenico
影响因子：
4.2
作者：
Chinnici, Cinzia M.;Yao, Yuemang;Pratico, Domenico
通讯作者：
Pratico, Domenico
影响因子：
10.5
作者：
Gandy S;DeKosky ST
通讯作者：
DeKosky ST
DOI：
10.1073/pnas.0308523101
发表时间：
2004-04-27
影响因子：
11.1
作者：
Mandal, AK;Skoch, J;Soberman, RJ
通讯作者：
Soberman, RJ