Microglial interactions with amyloid beta peptide

小胶质细胞与淀粉样β肽的相互作用

• 批准号: 6533878
• 负责人: Douglas Gordon Walker
• 金额: $ 25.14万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533878
• 关键词: Alzheimer's disease; amyloid proteins; biological signal transduction; brain cell; cell component structure /function; fibrinogen receptors; gene expression; gene induction /repression; human tissue; immunocytochemistry; immunologic techniques; inflammation; intermolecular interaction; laboratory rat; microglia; neurons; pathologic process; peptides; phagocytosis; plasminogen activator; postmortem; protein degradation; receptor binding; receptor expression; subtraction hybridization; urokinase

The objectives of this proposal are to characterize the consequences of the interaction of the Abeta peptide with human microglia. In the brains of individuals affected by AD, microglia are clustered around the Abeta plaques. A range of experimental data have shown that microglia become activated to a pro-inflammatory state as a result of an interaction with Abeta. These activated microglia are producing a range of toxic products that can be causing damage to the neurons. There are still many mechanisms involved in the interaction of microglia with Abeta that remain to be worked out. We have developed a unique model, employing microglia cells that are derived from postmortem human brains, to study these mechanisms. The first specific aim of this application will compare the activation properties of different types of Abeta peptides on microglia in terms of their induction of macrophage colony stimulating factor, monocyte chemotactic protein, neurotoxic factor, superoxide radicals and expression of the enzyme myeloperoxidase. We will also examine whether antibody coated Abeta peptides have the same effect on microglial activation, and determine the relative roles of potential Abeta receptors in mediating this activation. In specific aim 2, we will characterize the expression of the urokinase plasminogen activator receptor (uPAR) by microglia. This receptor plays a central role in coordinating the migration and adhesion of inflammatory cells and treatment of microglia with Abeta increases the expression of uPAR. In conjunction with this, we will determine whether the ligand urokinase plasminogen activator is induced and regulated in the same manner as the receptor. The consequences of binding to microglial uPAR will be investigated to characterize which signaling pathways are activated. In specific aim 3, we will use immunochemical and biochemical techniques to study what is happening to the Abeta peptide once it has interacted with microglia. Microglia appear to have only limited abilities to degrade the Abeta peptides over time once phagocytosed. We propose to study whether the peptide is degraded, is complexed or undergoes other modifications. With the availability of gene array and isolation techniques and human genetic data, in specific aim 4 we propose to discover new consequences of Abeta-microglial interactions. Overall, the findings from the proposed research could extend our knowledge of the inflammatory events occurring in the AD brain.

该提案的目的是描述 Abeta 肽与人类小胶质细胞相互作用的后果。 在 AD 患者的大脑中，小胶质细胞聚集在 Abeta 斑块周围。 一系列实验数据表明，小胶质细胞由于与 Abeta 相互作用而被激活至促炎状态。这些激活的小胶质细胞会产生一系列有毒产物，可能对神经元造成损害。 小胶质细胞与 Abeta 相互作用的许多机制仍有待研究。 我们开发了一种独特的模型，利用来自死后人类大脑的小胶质细胞来研究这些机制。 本申请的第一个具体目的是比较不同类型的 Abeta 肽对小胶质细胞的激活特性，包括诱导巨噬细胞集落刺激因子、单核细胞趋化蛋白、神经毒性因子、超氧自由基和髓过氧化物酶的表达。 我们还将检查抗体包被的 Abeta 肽是否对小胶质细胞激活具有相同的作用，并确定潜在的 Abeta 受体在介导这种激活中的相对作用。 在具体目标 2 中，我们将表征小胶质细胞尿激酶纤溶酶原激活剂受体 (uPAR) 的表达。该受体在协调炎症细胞的迁移和粘附方面发挥着核心作用，用 Abeta 治疗小胶质细胞会增加 uPAR 的表达。 与此相结合，我们将确定配体尿激酶纤溶酶原激活剂是否以与受体相同的方式被诱导和调节。 将研究与小胶质细胞 uPAR 结合的后果，以表征哪些信号通路被激活。 在具体目标 3 中，我们将使用免疫化学和生化技术来研究 Abeta 肽与小胶质细胞相互作用后会发生什么。 小胶质细胞一旦被吞噬，随着时间的推移，降解 Abeta 肽的能力似乎有限。 我们建议研究肽是否被降解、复合或经历其他修饰。 随着基因阵列和分离技术以及人类遗传数据的可用性，在具体目标 4 中，我们建议发现 Abeta-小胶质细胞相互作用的新后果。 总体而言，拟议研究的结果可以扩展我们对 AD 大脑中发生的炎症事件的了解。