The Neurobiology of 5-Lipoxygenase

描述（由申请人提供）：阿尔茨海默病（AD）是一种慢性和复杂的神经退行性疾病，导致认知功能进行性丧失并伴有痴呆症，并且无法治愈。衰老是阿尔茨海默病发生的一个重要危险因素，而失调的氧介导事件以及炎症过程被认为是衰老与疾病发病机制之间的潜在生物学联系。5-脂氧化酶（5-Lipoxygenases, 5LO）是一种氧化脂肪酸并由此合成炎症脂质介质（白三烯）和脂质过氧化产物（羟基过氧化物）的酶，两者都是强效氧化剂。这种酶在中枢神经系统（CNS）中广泛表达。然而，尽管一些间接证据表明它可能在神经退行性变中起作用，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5LO的表达水平在中枢神经系统中随着年龄的增长而增加，特别是在海马体中，与对照组相比，这种酶在AD大脑中上调。我们还证明了5LO基因消融导致野生型小鼠内源性A¿水平降低，Tg2576小鼠（ad样淀粉样变性小鼠模型）A¿沉积显著减少。此外，在细胞培养系统中，5LO激活和药物抑制分别导致A¿形成增加和减少。总之，这些数据有力地支持了这一酶途径可能在AD发病机制中发挥功能作用的假设，并代表了一种新的治疗靶点。本研究的主要目的是验证5LO激活导致生物活性脂质形成的假设，而生物活性脂质反过来调节与AD神经病理相关的代谢途径。阐明该酶系统影响A¿的产生和转换及其前体蛋白APP的代谢命运的分子和细胞机制非常重要，因为它可以建立与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，我们的研究结果将为未来研究特异性5LO抑制剂作为预防或限制AD演变和/或进展的新型治疗药物提供重要线索。

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.