5-lipoxygenase as an endogenous modulator of amyloid β formation in vivo.
5-lipoxygenase as an endogenous modulator of amyloid β formation in vivo.
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DOI：
10.1002/ana.22234
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发表时间：
2011-01
影响因子：
11.2
通讯作者：
Pratico, Domenico
中科院分区：
文献类型：
--
作者：
Chu, Jin;Pratico, Domenico
5-脂氧合酶（5-LO）酶途径广泛分布于中枢神经系统内，并且在阿尔茨海默病中上调。然而，它可能影响疾病发病机制的机制仍然难以捉摸。本研究从药理学和遗传学角度探讨了5-LO在体内外调节β淀粉样蛋白（Aβ）形成的分子机制。我们发现5-LO通过激活cAMP反应元件结合蛋白（CREB）调节Aβ的形成，而CREB反过来又增加γ-分泌酶复合物的转录。通过药理学抑制或显性失活突变体阻止CREB活化可阻断Aβ形成的5-LO依赖性升高以及γ-分泌酶mRNA和蛋白水平的增加。此外，5-LO靶向基因破坏或其体内选择性药理学抑制导致Aβ、CREB和γ-分泌酶水平显著降低。这些数据确立了5-LO在调节中枢神经系统内源性Aβ水平形成中的新功能作用。因此，5-LO药理学抑制可能有益于阿尔茨海默病的治疗和预防。
The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is up-regulated in Alzheimer's disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive. We evaluated the molecular mechanism by which 5-LO regulates Amyloid β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches. Here we show that 5-LO regulates the formation of Aβ by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the γ-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of Aβ formation and the increase of γ-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Aβ, CREB and γ-secretase levels. These data establish a novel functional role for 5-LO in regulating endogenous formation of Aβ levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer's disease.
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