Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice
Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice
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DOI：
10.1038/mp.2014.170
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发表时间：
2015-11-01
影响因子：
11
通讯作者：
Pratico, D.
中科院分区：
文献类型：
--
作者：
Chu, J.;Li, J-G;Pratico, D.
12/15-脂氧合酶（12/15 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，并且在淀粉样蛋白β（A β）-前体蛋白转基因小鼠（Tg 2576）的脑淀粉样变性的发展中起积极作用。本文研究了其药理学抑制作用对三转基因小鼠AD样表型的影响。与接受安慰剂的小鼠相比，用PD 146176（一种特异性12.15LO抑制剂）治疗的小鼠表现出记忆缺陷的显着改善。相同动物的A β水平和沉积显著降低，这继发于β-分泌酶途径的降低。此外，虽然两组的总tau蛋白可溶性水平没有变化，但PD 146176处理的小鼠其磷酸化状态和不溶性部分显著降低，这与应激活化蛋白激酶c-Jun N-末端激酶活性的降低特别相关。体外研究表明，对tau和A β的影响是相互独立的。这些数据确立了12.15LO在AD样表型的全谱发病机制中的功能作用，并代表了12.15LO抑制剂作为AD新型治疗剂的临床前开发的初始步骤的成功完成。
The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (A beta)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenicmice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12.15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in A beta levels and deposition, which was secondary to a decrease in the beta-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase.c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and A beta were independent from each other. These data establish a functional role for 12.15LO 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 12.15LO inhibitors as novel therapeutic agents for AD.