The neurobiology of 12/15 lipoxygenase

描述（由申请人提供）：阿尔茨海默病（AD）是一种悲剧性的常见和毁灭性的疾病，没有有效的治疗方法。虽然导致该疾病的病因尚不清楚，但越来越明显的是，炎症和氧化应激是AD脑的特征。衰老是发展AD的最强风险因素之一，并且氧介导的事件被认为是负责衰老中增加的神经元脆弱性的可能机制。脂氧合酶（LO）是能够将氧插入花生四烯酸分子中并由此合成炎性类花生酸或形成脂质过氧化产物的酶。在中枢神经系统（CNS）中最丰富的LO之一是神经元12/15 LO，其活性和蛋白水平在AD中与对照脑相比增加。然而，尽管一些间接证据表明，这种酶可能在神经变性中发挥作用，但12/15 LO在CNS中的生物学作用尚未确定。 本提案的长期目标是了解CNS中12/15 LO的重要性，特别强调AD。AD-淀粉样变性（Tg 2576）的一个良好的特点，小鼠模型的可用性与12/15 LO酶活性的特异性抑制剂，和小鼠遗传缺陷的12/15 LO基因表达应该让我们阐明这一临床相关的问题。在具体目标1中，我们将研究12/15 LO活性的药理学抑制是否对Tg 2576的表型有任何影响，然后我们将通过12/15 LO缺陷小鼠与Tg 2576杂交来确认这些结果。在具体目标2中，我们将表征在原代神经元中调节12/15 LO表达的细胞和分子因子，并将研究这种酶途径与AD的淀粉样蛋白假说之间的关系。 总之，这些研究将阐明12/15 LO代谢途径的神经生物学及其在AD发病机制中的假定作用。这些数据是临床相关的，并应提供重要的线索，潜在的使用特定的12/15 LO抑制剂作为新的治疗药物，用于预防或限制AD的演变和/或进展。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a tragically common and devastating illness for which there is no effective therapy. Although the causative event(s) responsible for the disease are not known, it is more and more evident that inflammation and oxidative stress are features of AD brains. Aging is one of the strongest risk factors for developing AD, and oxygen-mediated events are being considered as possible mechanisms responsible for the increasing neuronal vulnerability in aging. Lipoxygenases (LO) are enzymes that can insert oxygen into a molecule of arachidonic acid and thereby synthesize inflammatory eicosanoids or form lipid peroxidation products. One of the most abundant LO in the central nervous system (CNS) is neuronal 12/15LO, whose activity and protein levels are increased in AD compared to control brains. However, despite some circumstantial evidence suggesting that this enzyme might play a role in neurodegeneration, a biological role for 12/15LO in the CNS has yet to be established. The long-term objective of this proposal is to understand the importance of 12/15LO in the CNS with particular emphasis on AD. The availability of a well-characterized mouse model of AD-amyloidosis (Tg2576) together with a specific inhibitor of the 12/15LO enzyme activity, and mice genetically deficient for 12/15LO gene expression should allow us to elucidate this clinically relevant issue. In Specific Aim 1 we will investigate whether pharmacological inhibition of 12/15LO activity has any effect on the phenotype of Tg2576, then we will seek confirmation of these results by cross-breeding mice deficient for 12/15LO with Tg2576. In Specific Aim 2 we will characterize cellular and molecular factors that regulate the expression of 12/15LO in primary neurons, and will investigate the relationship between this enzymatic pathway and the amyloid hypothesis of AD. In summary, these studies will elucidate the neurobiology of the 12/15LO metabolic pathway and its putative role in AD pathogenesis. Such data are clinically relevant and should provide important clues to the potential use of specific 12/15LO inhibitors as novel therapeutic agents for preventing or limiting the evolution and/or progression of AD.