Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice.
Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice.
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DOI：
10.1016/j.neurobiolaging.2014.05.016
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发表时间：
2014-11
影响因子：
4.2
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Di Meco A;Lauretti E;Vagnozzi AN;Praticò D
5-脂氧合酶（5LO）在阿尔茨海默病（AD）中上调，用齐留通对其进行药理学阻断可减缓年轻AD小鼠中AD样表型的发展。然而，其在AD病理学确立后的疗效尚不清楚。为此，从12月龄开始，三重转基因小鼠（3xTg）接受齐留通（一种选择性5LO抑制剂）或安慰剂3个月，然后评估这种治疗对行为、淀粉样蛋白和tau病理学的影响。虽然服用安慰剂的小鼠表现出记忆力恶化，但治疗小鼠的表现甚至比基线更好。与安慰剂相比，给药小鼠的Aβ沉积和tau磷酸化显著减少，分别继发于γ-分泌酶和CDK-5活化减少。我们的数据提供了新的见解，疾病的改善作用，抑制5LO作为一个可行的AD治疗方法。它们代表了成功完成临床前研究，以开发这类药物作为该疾病的临床适用疗法。
The enzyme 5-lipoxygenase (5LO) is up-regulated in Alzheimer’s disease (AD), and its pharmacological blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12-months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid and tau pathology assessed. While mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significant less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease.
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