Giannopoulos P F, Chu J, Joshi Y B, Sperow M, Li J-G, Kirby L G, Praticò D
1] Center for Translational Medicine and Temple University School of Medicine, Philadelphia, PA, USA [2] Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
Mol Psychiatry. 2014 Apr;19(4):511-8. doi: 10.1038/mp.2013.23. Epub 2013 Mar 12.
5-Lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD) and in vivo modulates the amyloidotic phenotype of amyloid precursor protein transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue, we used a genetic and a pharmacological approach by generating 3 × Tg mice deficient for 5LO and administering 3 × Tg mice with a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life, these mice had a significant reduction of Aβ and tau pathology. Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.
5-脂氧合酶（5LO）在阿尔茨海默病（AD）中表达上调，并且在体内可调节淀粉样前体蛋白转基因小鼠的淀粉样变性表型。然而，关于5LO对突触功能、完整性和认知的影响尚无相关数据。为解决这一问题，我们采用了遗传学和药理学方法，构建了5LO基因缺陷的3×Tg小鼠，并给3×Tg小鼠施用5LO抑制剂。与对照组相比，我们发现即使在明显的神经病理学出现之前，这两种动物均表现出显著的记忆改善、突触功能障碍的恢复以及突触完整性的改善。此外，在生命后期，这些小鼠的Aβ和tau病理学显著减轻。我们的研究结果支持5LO在调节突触可塑性和记忆方面具有新的功能作用。它们证实该蛋白是AD表型全谱发展的多效性因素，使其成为AD治疗的有效靶点。
