Oxylipins, aging and Alzheimer’s disease

阿尔茨海默病（AD）约占痴呆症病例总数的三分之二，AD病例数量 预计到2050年将增长三倍。确定一种调节AD的新途径不仅可以改善我们的研究， 了解神经变性背后的机制，而且还将显着提高生活质量 的老年人口。最近的人体研究揭示了omega-3脂肪酸水平与 欧米茄-6饮食脂质和大脑老化。然而，这些影响背后的具体途径仍然存在， 大部分未知。该提案的总体目标是阐明omega-3和omega-6的作用 多不饱和脂肪酸（PUFA）代谢产物在AD中的作用。ω-3和ω-6多不饱和脂肪酸的代谢产生 通过花生四烯酸（AA）级联，数百种称为氧脂的脂质信号分子。这些氧脂素 在炎症、血压调节、血管生成和纤维化中起稳态作用， 水平受到疾病进展的显著影响。此外，最近的研究表明， 氧化脂质在AD中可能起重要作用。Aβ和tau蛋白的沉积是AD的标志， AD的主要危险因素之一。因此，在这个提议中，我们假设Aβ和tau蛋白的沉积， 衰老调节体内氧脂素水平，这影响动物的神经元健康。 为了验证我们的假设，我们将开发一种多学科的方法， 分析化学家，神经生物学家，AD研究人员和模式生物的使用。我们将1）建立 CYP 450 PUFA代谢产物的内源性水平与Aβ-、tau-和衰老效应之间的关系 诱导的神经退行性变; 2）确定特异性氧脂素对Aβ-、tau-和衰老诱导的神经退行性变的影响。 神经变性我们将使用秀丽隐杆线虫（C. elegans）作为模式生物来研究 Aβ和tau，与衰老对PUFA代谢的影响因易产生大的年龄同步性 人口，以及可用于开展这项研究的现有遗传工具的数量。而且很多 衰老和神经退行性途径以及氧化脂质途径在C. elegans优雅and humans人类. 我们将使用最先进的超高效液相色谱和串联质谱联用技术， 测定C.在有机体的整个生命周期中以及在转基因菌株中， 过表达Aβ和tau。我们将测试受Aβ沉积显著影响的氧化脂质的作用， 在使用过表达Aβ和tau的转基因菌株的神经退行性测定中，一旦成功 通过这个项目，我们可以确定一个对衰老和神经变性研究很重要的新途径。我们的结果 也可以解释omega-3和omega-6 PUFA对衰老的影响。

Alzheimer’s disease (AD) comprises about two-thirds of the total dementia cases, and the number of AD cases is expected to triple by 2050. Identifying a new pathway that modulates AD will not only improve our understanding of the mechanism behind neurodegeneration, but will also significantly improve the quality of life of the aged population. Recent human studies revealed a causal relationship between the levels of omega-3 and omega-6 dietary lipids and aging of the brain. However, the specific pathway(s) behind such effects remains largely unknown. The overall goal of this proposal is to elucidate the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) metabolites in AD. Metabolism of omega-3 and omega-6 PUFAs generates hundreds of lipid-signaling molecules called oxylipins through the arachidonic acid (AA) cascade. These oxylipins play a homeostatic role in inflammation, blood pressure regulation, angiogenesis, and fibrosis, and their in vivo levels are significantly affected by disease progression. Furthermore, recent studies suggested that specific oxylipins may play an important role in AD. The deposition of Aβ and tau are hallmarks of AD, and aging remains one of the key risk factors of AD. Therefore, in this proposal, we hypothesize that deposition of Aβ and tau and aging modulate the in vivo oxylipin levels, which affects the neuronal health of animals. To test our hypothesis, we will develop a multidisciplinary approach by assembling expertise from organic and analytical chemists, neurobiologists, AD researchers and the use of a model organism. We will 1) establish the relationship between endogenous levels of CYP450 PUFA metabolites and the effect of Aβ-, tau-and aging- induced neurodegeneration and; 2) determine the effect(s) of specific oxylipins on Aβ-, tau-and aging induced neurodegeneration. We will use Caenorhabditis elegans (C. elegans) as a model organism to study the effect of Aβ and tau, and aging on PUFA metabolism because of the ease of generating large age-synchronized populations, and the number of established genetic tools available to carry out this research. Furthermore, many aging and neurodegenerative pathways and oxylipin pathways are conserved between C. elegans and humans. We will use state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry to determine oxylipins levels in C. elegans over the lifespan of the organism and in transgenic strains that overexpress Aβ and tau. We will test the effect of oxylipins that are significantly affected by deposition of Aβ and tau and aging in neurodegenerative assays using transgenic strains that overexpress Aβ and tau. Upon success of this project, we could identify a new pathway important for aging and neurodegeneration research. Our results could also explain the effect(s) of omega-3 and omega-6 PUFAs on aging.