Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model Involvement of γ-Secretase
Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model Involvement of γ-Secretase
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DOI：
10.1016/j.ajpath.2010.12.032
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发表时间：
2011-04-01
影响因子：
6
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）广泛分布于中枢神经系统。先前的工作表明，这种蛋白质在阿尔茨海默病（AD）中上调，并且其遗传缺失导致Tg 2576小鼠中淀粉样蛋白β（A β）水平降低。在本研究中，我们研究了5-LO药理学抑制对这些小鼠淀粉样变性表型的影响。与接受载体的对照Tg 2576小鼠相比，接受齐留通（一种选择性和特异性5-LO抑制剂）的小鼠脑中的β沉积显著减少。这种降低与脑A β肽水平的类似降低相关。齐留通治疗未诱导淀粉样β前体蛋白（APP）、BACE 1或ADAM 10的稳态水平发生任何变化。相比之下，它导致早老素1（PSEN 1，别名PS1），nicastrin（NCCs），早老素增强子2同源物（PSNEN，别名Pen-2）和前咽缺陷1（APH-1）的显着减少，这是γ-分泌酶复合物的四种组分-在蛋白质和信息水平上。此外，体外研究证实，齐留通通过调节γ-分泌酶复合物水平而不影响Notch信号传导来防止A β形成。这些数据确立了5-LO在AD样淀粉样变性发病机制中的功能作用，从而调节γ-分泌酶途径。他们认为，5-LO的药理学抑制可以为AD提供新的治疗机会。(Am J Pathol 2011，178：1762-1769; DOI：10.1016/j.ajpath.2010.12.032）
The 5-lipoxygenase (5-LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD) and that its genetic absence results in a reduction of amyloid beta (A beta) levels in Tg2576 mice. In the present study, we examined the effect of 5-LO pharmacological inhibition on the amyloidotic phenotype of these mice. A beta deposition in the brains of mice receiving zileuton, a selective and specific 5-LO inhibitor, was significantly reduced when compared with control Tg2576 mice receiving vehicle. This reduction was associated with a similar decrease in brain A beta peptides levels. Zileuton treatment did not induce any change in the steady state levels of amyloid-beta precursor protein (APP), BACE1 or ADAM10. By contrast, it resulted in a significant reduction of presenilin 1 (PSEN1, alias PS1), nicastrin (NCSTN), presenilin enhancer 2 homolog (PSNEN, alias, Pen-2), and anterior pharynx defective 1 (APH-1), the four components of the gamma-secretase complex-at the protein and message level. Furthermore, in vitro studies confirmed that zileuton prevents A beta formation by modulating gamma-secretase complex levels without affecting Notch signaling. These data establish a functional role for 5-LO in the pathogenesis of AD-like amyloidosis, whereby it modulates the gamma-secretase pathway. They suggest that pharmacological inhibition of 5-LO could provide a novel therapeutic opportunity for AD. (Am J Pathol 2011, 178:1762-1769; DOI: 10.1016/j.ajpath.2010.12.032)