Interleukin 1alpha polymorphism and Alzheimer's disease

白细胞介素1α多态性与阿尔茨海默病

• 批准号: 6651535
• 负责人: YANSHENG DU
• 金额: $ 22.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651535
• 关键词: African American; Alzheimer's disease; blood chemistry; cell line; cerebrospinal fluid; clinical research; disease /disorder onset; disease /disorder proneness /risk; enzyme linked immunosorbent assay; family genetics; genetic polymorphism; genotype; human genetic material tag; human subject; interleukin 1; intermolecular interaction; interview; lipopolysaccharides; neuropsychological tests; pathologic process; patient oriented research; polymerase chain reaction; transfection

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.

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学的发病级联事件。神经炎症的诱导涉及星形胶质细胞和小胶质细胞的活化，随后是许多细胞因子的表达。在细胞外淀粉样蛋白斑块周围的区域发现了产生促炎细胞因子如白细胞介素-1 a（IL-1 α）、白细胞介素-1 B（IL-1 β）和白细胞介素-6（IL-6）的活化的小胶质细胞。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引发连锁反应，导致神经毒性细胞因子的释放增强，淀粉样蛋白沉积和随后的神经炎淀粉样蛋白斑块形成。在AD脑中发现的IL-1蛋白的升高的组织水平以及活化的IL-1免疫反应性星形胶质细胞的增加的数量两者表明IL-1过表达以及因此细胞因子周期的扩增可能是发展AD的致病事件。最近，我们和其他人报道IL-1A（-889）等位基因2在牙周炎和AD患者中过度表达。我们建议通过证实我们队列中IL-1多态性之间的先前描述的相互作用，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AD患者队列中IL-1A（-889）等位基因2的发生率，继续并扩展本研究。我们还建议通过研究这种多态性可能对IL-1 α的调节产生的影响来表征潜在的生理学相关变化（例如比较等位基因1和等位基因2多态性的启动子活性）。该提案的总体目标是： 1.确认IL-1A（-889）、IL-1B（3953）和/或IL-1 RA单独或共同（相互作用）是否会增加我们队列中的风险，如其他组所报告的那样。此外，我们将分析IL-1A（-889）与AD发病年龄和疾病进展率之间的关系。2.研究IL-1A（-889）多态性是否增加家族性AD和非裔美国人的风险。3.确定位于IL-1A基因启动子区的IL-1A（-889）在刺激条件（LPS和ABeta）下是否导致活性增加。研究IL-1A（-889）多态性纯合子个体（正常和AD患者）的CSF和血浆IL-1 a/B蛋白水平是否显著增加。此外，我们将研究来自IL-1A（-889）多态性纯合个体的全血在随后的LPS或Ab刺激下对IL-1 α/β分泌的影响是否比来自野生型纯合个体的全血响应更大的程度。我们专注于IL-1A（-889），因为这种多态性赋予AD的风险已在我们的队列中得到证实。本工作的意义在于，表征IL-1A（-889）多态性及其与AD的关系以及理解其发病机制可能有助于开发抗炎和抗痴呆药物以及靶向潜在的治疗方法。