Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Biol Psychiatry. 2013 Sep 1;74(5):348-56. doi: 10.1016/j.biopsych.2013.04.009. Epub 2013 May 15.
5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer's disease (AD) with plaques and tangles (i.e., 3xTg mice).
By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3xTg mice.
We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway.
Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.
5-脂氧合酶激活蛋白（FLAP）在中枢神经系统中大量存在。尽管其在周围炎症中的功能已被广泛研究，但该蛋白在中枢神经系统中的新作用正在出现。我们的研究目的是研究 FLAP 在具有斑块和缠结（即 3xTg 小鼠）的阿尔茨海默病（AD）小鼠模型中的功能作用。
通过实施 FLAP 的基因敲除和 FLAP 抑制剂（MK-591）的药理抑制，我们评估了其对 3xTg 小鼠的 AD 样神经病理学、认知和突触可塑性的影响。
我们表明，减少 FLAP 可改善认知和记忆，并在明显神经病理学发展之前的早期挽救突触功能障碍。FLAP 的基因敲除和药理抑制也通过 γ-分泌酶途径减少 Aβ和通过 cdk5 途径减少 tau 磷酸化，从而改善 AD 病理学。
我们的研究确定了 FLAP 在调节记忆和突触可塑性中的新功能作用。它们将该蛋白定位在多条途径的交汇点，这些途径最终导致整个 AD 样表型的发展，使其成为一种具有疾病修饰能力的可行治疗靶点，可用于治疗这种疾病。
