Dissecting the role of 5LO in neurodegeneration associated with homocysteine

 描述（由申请人提供）：阿尔茨海默病（AD）是老年人中最常见的与痴呆相关的慢性神经退行性疾病，影响约6-8%的年龄>65岁的人。虽然目前尚无有效的治疗方法，但通过干预措施控制与疾病发病有关的风险因素，仍可能减少病例数量，并造成巨大的经济损失。这一事实促使人们做出巨大努力，以确定这些因素，并开发治疗方法来减少和/或预防这些因素。同型半胱氨酸（Hcy）水平的异常升高被认为是显著增加发展成AD的可能性的危险因素。然而，这种生物学效应涉及的机制仍有待充分研究。我们的初步数据表明，Hcy特异性上调5脂氧合酶（5LO），这是一种在脑中广泛表达的蛋白质，它调节Aβ形成和tau代谢，并且5LO是继发于Hcy的AD样表型变化所必需的。总之，这些发现为我们的工作假设提供了理论基础和生物学基础：Hcy激活5LO通路，然后导致Aβ肽的异常形成，过度的tau磷酸化和认知缺陷。我们将通过研究5LO在Aβ和tau神经病理学发展中的重要作用，以及在Hcy升高的慢性条件下AD转基因小鼠模型中的行为缺陷来验证这一假设。我们接下来将研究Hcy通过5LO调节神经细胞中Aβ/APP加工和tau代谢的机制。最后，我们将通过药理学和遗传学方法在体内确定这些机制。我们的研究是新颖的和有意义的，因为他们将建立一个生物联系的背景下，AD的发病机制Hcy和5LO。他们还将为Hcy的神经生物学提供新的机制知识，并为携带这种疾病风险因素的个体的新治疗方法提供有用的线索。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with dementia in the elderly, affecting approximately 6-8% all person aged >65 years. Although an effective treatment for the disease is unavailable, intervention to control risk factors implicated in the disease onset can still redue the number of cases and the associated enormous economic cost. This fact has stimulated a large effort to identify those factors and to develop treatments to reduce and/or prevent them. Abnormal elevation of homocysteine (Hcy) levels is considered a risk factor that significantly increases the probability to develop AD. However, the mechanism(s) involved in this biologic effect remain to be fully investigated. Our preliminary data demonstrate that Hcy specifically up-regulates 5Lipoxygenase (5LO), a protein widely expressed in the brain where it modulates Aβ formation and tau metabolism, and that 5LO is required for the changes in the AD-like phenotype secondary to Hcy. Taken together, these findings provide the rationale and biologic basis of our working hypothesis: Hcy activates the 5LO pathway, which then results in an abnormal formation of Aβ peptides, an excessive tau phosphorylation and cognitive deficits. We will test this hypothesis by studying the essential role of 5LO in the development of the Aβ and tau neuropathologies, and behavior deficits in transgenic mouse models of AD during a chronic condition of elevated Hcy. We will next investigate the mechanisms whereby Hcy via the 5LO modulates Aβ/APP processing and tau metabolism in neuronal cells. Finally, we will ascertain these mechanisms in vivo by using a pharmacologic and a genetic approach. Our studies are novel and significant because they will establish a biological link between Hcy and 5LO in the context of the AD pathogenesis. They also will provide new mechanistic knowledge into the neurobiology of Hcy, and useful clues for new therapeutic approaches in individuals carrying this risk factor for developing the disease.