Interleukin 1alpha polymorphism and Alzheimer's disease

描述(由申请人提供)：越来越多的研究表明，炎症过程参与了导致阿尔茨海默病脑病理的一连串致病事件。神经炎症的诱导涉及星形胶质细胞和小胶质细胞的激活，随后一些细胞因子的表达。在细胞外淀粉样斑块周围发现激活的小胶质细胞产生促炎细胞因子，如IL-1α(IL-1α)、IL-1β(IL-1β)和IL-6(IL-6)。由于AD患者的大脑中没有急性感染的迹象，这些细胞因子的慢性产生可能会引发连锁反应，导致神经毒性细胞因子的增强释放，淀粉样蛋白沉积，以及随后的神经性淀粉样斑块形成。阿尔茨海默病患者脑组织中IL-1蛋白水平的升高和激活的IL-1免疫反应星形胶质细胞数量的增加都表明，IL-1的过度表达和细胞因子周期的放大可能是AD发生的原因之一。最近，我们和其他人报道了IL-1A(-889)等位基因2在牙周炎和AD患者中的过度表达。我们建议继续并扩展这项研究，通过证实先前在我们的队列中IL-1多态之间的相互作用，并调查与年龄/性别匹配的对照组相比，家族性AD和非裔美国人AD患者队列中IL-1A(-889)等位基因2的发生率。我们还建议通过研究等位基因1和等位基因2的多态对IL-1α调节的影响来表征潜在的生理相关变化(例如比较等位基因1和等位基因2的多态启动子的活性)。这项提案的总体目标是： 1.确定IL-1a(-889)、IL-1B(3953)和/或IL-1RA单独或共同(相互作用)是否会增加我们队列中的风险，正如其他组报告的那样。此外，我们还将分析IL-1a(-889)与AD发病年龄和疾病进展率的关系。2.研究IL-1a(-889)基因多态性是否会增加家族性AD和非裔美国人的风险。3.研究位于IL-1a基因启动子区域的IL-1a(-889)是否在刺激条件下(脂多糖和ABeta)导致活性升高。4.研究IL-1a(-889)纯合子个体脑脊液和血浆中IL-1a/b蛋白水平是否显著升高(无论在正常人群还是AD患者)。此外，我们将研究IL-1a(-889)纯合子个体的全血是否比野生型纯合子个体的全血在随后的内毒素或抗体刺激下对IL-1α/β分泌的影响更大。我们将重点放在IL-1a(-889)上，因为我们的队列中已经证实了这种导致AD风险的基因多态。这项工作的意义在于，表征IL-1a(-889)基因多态性及其与阿尔茨海默病的关系，了解其发病机制，有助于开发抗炎和抗痴呆药物，并有针对性地进行潜在的治疗。

DESCRIPTION (provided by applicant): An increasing number of studies have suggested that inflammatory processes take part in the pathogenetic cascade of events that leads to Alzheimer's disease brain pathology. Induction of neuroinflammation involves the activation of astrocytes and microglial cells followed by the subsequent expression of a number of cytokines. Activated microglia producing proinflammatory cytokines such as interleukin-1 a (IL-1 alpha), interleukin-1 b (IL-1 Beta), and interleukin-6 (IL-6) have been found in areas surrounding extracellular amyloid plaques. Because there are no signs of acute infection in the brains of AD patients, chronic production of these cytokines may initiate a chain reaction that leads to enhanced release of neurotoxic cytokines, amyloid deposition, and subsequent neuritic amyloid plaque formation. Both elevated tissue levels of the IL-1 protein as well as increased number of activated IL-1 immunoreactive astrocytes found in AD brain suggest that IL-1 overexpression and thus amplification of a cytokine cycle may be a causative event to develop AD. Recently we and others reported that the IL-1A(-889) allele 2 is over-represented in patients with periodontitis as well as AD. We propose to continue and extend this study by confirming previously described interactions among the IL-1 polymorphisms in our cohort and investigating the incidence of the IL-1A(-889) allele 2 in cohorts of familial AD and African American AD patients compared to age/gender matched controls. We also propose to characterize potentially physiologically relevant changes (such as comparing the activities of promoters from allele 1 and allele 2 polymorphisms) by investigating the effects of this polymorphism may have on the regulation of IL-1 alpha. The overall goals of this proposal are: 1. To confirm whether or not IL-1A(-889), IL-1B(3953) and/or IL-1RA alone or together (interactions) increase the risk in our cohort as has been reported by other groups. Additionally, we will analyze relationships between IL-1A(-889) and the age of AD onset and rate of disease progression. 2. To investigate whether or not the IL-1A(-889) polymorphism confers an increase risk in cohorts of familial AD and African Americans. 3.To determine if lL-1A(-889), located in the promoter region of the IL-1A gene, results in increased activity under stimulatory conditions (LPS and ABeta) 4. To investigate whether or not there is a significant increase in CSF and plasma levels of the IL-1 a/b proteins in individuals homozygous for the IL-lA (-889) polymorphism (in both normal and patients with AD). Furthermore, we will investigate if whole blood from individuals homozygous for the IL-1A(-889) polymorphism responds to a greater extent than whole blood from a wild type homozygote individual under following stimulation by LPS or Ab for effects on IL-1 a/Beta secretion. We focus on IL-1A(-889) as this polymorphism conferring a risk to develop AD has been confirmed in our cohort. The significance of this work is that characterization of the IL-lA (-889) polymorphism and its relationship to AD as well as understanding its pathogenetic mechanism may aid in developing anti-inflammatory and anti-dementia drugs as well as targeting potential therapeutic treatments.