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。虽然导致该疾病的致病事件尚不清楚，但越来越明显的是，炎症和氧化应激是AD大脑的特征。衰老是阿尔茨海默病发生的最强危险因素之一，氧介导的事件被认为是导致衰老过程中神经元易感性增加的可能机制。脂氧化酶（LO）是一种能够将氧插入花生四烯酸分子中，从而合成炎性类二十烷化合物或形成脂质过氧化产物的酶。中枢神经系统（CNS）中最丰富的LO之一是神经元12/15LO，与对照大脑相比，AD患者的活性和蛋白质水平升高。然而，尽管一些间接证据表明该酶可能在神经退行性变中起作用，但12/15LO在中枢神经系统中的生物学作用尚未确定。

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.