The Neurobiology of 5-Lipoxygenase

描述(申请人提供)：阿尔茨海默病(AD)是一种慢性复杂的神经退行性疾病，会导致痴呆症患者认知功能的进行性丧失，目前还没有治愈的方法。衰老是发展为阿尔茨海默病的重要危险因素，氧介导的失调事件以及炎症过程被认为是衰老与疾病发病机制之间潜在的生物学联系。5-脂氧合酶(5LO)是一种氧化脂肪酸从而合成炎性脂质介质(白三烯)和脂质过氧化产物(羟基过氧化产物)的酶，这两种物质也是有效的氧化剂。这种酶广泛表达于中枢神经系统(CNS)。然而，尽管一些间接证据表明5LO可能在神经退行性变中发挥作用，但5LO在中枢神经系统中的确切生物学作用尚未确定。我们最近发现，随着年龄的增长，5LO在中枢神经系统中的表达水平增加，特别是在海马区，与对照组相比，该酶在AD大脑中上调。我们还证明，5LO的遗传消融导致野生型小鼠内源性A？水平降低，并显著减少Tg2576小鼠的A？沉积，Tg2576小鼠是AD样淀粉样变性的小鼠模型。此外，在细胞培养系统中，5LO激活和药物抑制分别导致A？的形成增加和减少。综上所述，这些数据为这一酶途径可能在AD发病机制中发挥作用的假说提供了强有力的支持，并代表了该疾病的新的治疗靶点。目前该方案的主要目的是验证5LO激活导致生物活性脂类形成的假说，生物活性脂类反过来调节与AD神经病理密切相关的代谢途径。阐明这种酶系统影响Aβ的产生和周转及其前体蛋白APP的代谢命运的分子和细胞机制是非常重要的，因为它可以建立一条与AD病理发展相关的新途径，并成为新的治疗靶点。因此，如果成功，我们的发现将为未来研究特定的5LO抑制剂作为预防或限制AD演变和/或进展的新型治疗剂提供重要线索。 公共卫生相关性：阿尔茨海默病(AD)是一种导致认知功能急剧丧失的疾病，影响着全球数百万老年人。然而，它的病因(S)仍然未知，也没有治愈的方法。5脂氧合酶(5LO)是阿尔茨海默病患者脑内脂肪氧合酶(5LO)的一种蛋白，其表达水平和活性均高于正常对照组，可能直接参与AD的发生发展。如果我们证实了这一假设，我们的发现将为未来使用5LO的特定药物抑制剂作为治疗这种毁灭性疾病的新疗法的人类研究提供重要信息。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic and complex neurodegenerative disease that causes progressive loss of cognitive functions with dementia and for which there is no cure. Aging is a strong risk factor for developing AD, and dysregulated oxygen-mediated events as well as inflammatory processes are considered potential biological links between aging and the disease pathogenesis. 5-Lipoxygenases (5LO) is an enzyme that oxidizes fatty acids and thereby synthesizes inflammatory lipid mediators (leukotrienes), and lipid peroxidation products (hydroxyperoxides), both of which are also potent oxidants. This enzyme is widely expressed in the central nervous system (CNS). However, despite some circumstantial evidence suggesting that it may play a role in neurodegeneration, a definitive biological role for 5LO in the CNS has yet to be established. We recently showed that the expression levels of 5LO are increased in the CNS with aging particularly in the hippocampus, and that compared to controls this enzyme is upregulated in AD brains. We also demonstrated that genetic ablation of 5LO results in reduced endogenous A¿ levels in wild type mice, and significantly less A¿ deposits in the Tg2576 mice, a mouse model of AD-like amyloidosis. Further, in cell culture systems 5LO activation and pharmacologic inhibition results in increased and reduced A¿ formation, respectively. Together, these data provide strong support for the hypothesis that this enzymatic pathway could play a functional role in AD pathogenesis, and represent a novel therapeutic target for the disease. The main goal of the current proposal is to test the hypothesis that 5LO activation results in the formation of bioactive lipids, which in turn modulate metabolic pathways germane to the AD neuropathology. The elucidation of the molecular and cellular mechanisms whereby this enzyme system influences the production and turnover of A¿ and the metabolic fate of its precursor protein, APP, is extremely important since it could establish a novel pathway relevant to the development of AD pathology, and become a new therapeutic target. Thus, if successful, our findings will provide important clues for future studies with specific 5LO inhibitors as novel therapeutic agents for preventing or limiting the evolution and /or progression of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a disease that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its cause(s) remain unknown, and there is no cure for it. 5Lipoxygenase (5LO) is a protein whose levels and activity are increased in AD compared with healthy control brain, and could be directly involved in the development of the disease. If we prove this hypothesis, our findings will provide important information for future human studies with specific drug inhibitors of 5LO as a novel therapy for the treatment of this devastating disease.