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首页> 外文期刊>Biological psychiatry >5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer's disease
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5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer's disease

机译：5-脂氧合酶激活蛋白的减少可改善阿尔茨海默氏病小鼠模型的认知缺陷，突触功能障碍和神经病理学

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Background 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). Methods 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. Results 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. Conclusions 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.
机译：背景5-脂氧合酶激活蛋白（FLAP）大量存在于中枢神经系统中。尽管在周围发炎的情况下已对其功能进行了广泛的研究，但该蛋白在中枢神经系统中正在发挥新作用。我们研究的目的是研究FLAP在具有斑块和缠结的阿尔茨海默氏病（AD）小鼠模型（即3xTg小鼠）中的功能作用。方法通过实施FLAP的基因敲除和FLAP抑制剂（MK-591）的药理抑制作用，我们评估了对3xTg小鼠AD样神经病理学，认知和突触可塑性的影响。结果我们显示，FLAP的降低可导致认知和记忆的改善，以及在明显的神经病理学发展之前的早期抢救突触功能障碍。遗传敲除和FLAP的药理抑制作用还可以通过γ-分泌酶途径减少Aβ和通过cdk5途径减少tau磷酸化来改善AD病理。结论我们的研究确定了FLAP在调节记忆和突触可塑性中的新功能作用。他们在多种途径的十字路口建立了这种蛋白质，最终促进了整个AD样表型的发展，使其成为具有治疗疾病能力的可行的治疗靶标。

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