5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.
5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.
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DOI：
10.1002/ana.23642
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发表时间：
2012-09
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;Giannopoulos, Phillip F.;Ceballos-Diaz, Carolina;Golde, Todd E.;Pratico, Domenico
5-脂氧合酶（5LO）在阿尔茨海默病（AD）中上调，其遗传缺失降低了APP小鼠中的Aβ水平。然而，其在调节tau神经病理学中的功能作用仍有待阐明。为此，我们产生过表达神经元5LO的三重转基因小鼠（3xTg-AD）并研究其表型。与对照组相比，过表达5LO的3xTg-AD小鼠表现出记忆缺陷、斑块和缠结病理的恶化。Aβ的升高继发于γ-分泌酶途径的上调，而tau蛋白过度磷酸化是由Cdk 5激酶的激活引起的。体外研究证实该激酶参与了5-LO依赖的tau蛋白磷酸化，且与Aβ的作用无关。我们的研究结果强调了神经元5LO在加剧AD相关tau病理中的新功能作用。他们提供了关键的临床前证据，证明测试选择性5LO抑制剂治疗AD是合理的。
The 5-lipoxygenase (5LO) enzyme is up-regulated in Alzheimer’s disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated. To this end, we generated triple transgenic mice (3xTg-AD) over-expressing neuronal 5LO and investigated their phenotype. Compared with controls, 3xTg-AD mice over-expressing 5LO manifested an exacerbation of memory deficits, plaques and tangles pathologies. The elevation in Aβ was secondary to an up-regulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5-LO-dependent tau phosphorylation, which was independent of the effect on Aβ. Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.
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影响因子：
11.2
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