Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.
Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.
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DOI：
10.1371/journal.pone.0070991
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Chu J;Li JG;Praticò D
5-脂氧合酶(5LO)广泛分布于中枢神经系统。以往的研究表明，该蛋白在阿尔茨海默病(AD)中表达上调，并在APP转基因小鼠脑淀粉样变性的发生发展中发挥积极作用。在本文中，我们研究了其药理抑制对斑块和缠结小鼠3×Tg小鼠整个AD样表型的影响。与接受安慰剂治疗的小鼠相比，接受5LO特异性抑制剂齐鲁通治疗的小鼠的记忆损伤表现出显著的改善。同一组动物的Aβ水平和沉积显著减少，这是由于γ-分泌酶途径下调所致。此外，虽然两组的总tau水平没有变化，但齐留通治疗的小鼠的磷酸化状态和不溶形式显著减少，其次是CDK5激酶的激活减少。这些数据确立了5LO在全谱AD样表型的发病机制中的功能作用，并代表着5LO抑制剂作为可行的AD治疗剂的临床前开发的第一步的成功完成。
The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer’s disease (AD), and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3×Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.
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影响因子：
11.2
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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