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Microglial interactions with amyloid beta peptide

小胶质细胞与淀粉样β肽的相互作用

基本信息

批准号：
6645338
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
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2004-11-30
项目状态：
已结题

项目摘要

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.

本提案的目的是表征β肽与人类小胶质细胞相互作用的后果。在阿尔茨海默症患者的大脑中，小胶质细胞聚集在β斑块周围。一系列实验数据表明，小胶质细胞被激活到促炎状态是与β相互作用的结果。这些被激活的小胶质细胞会产生一系列有毒物质，对神经元造成损害。小胶质细胞与β的相互作用仍有许多机制有待研究。我们开发了一个独特的模型，利用从死后人类大脑中提取的小胶质细胞来研究这些机制。本应用程序的第一个具体目的是比较不同类型的Abeta肽在小胶质细胞上的激活特性，包括它们对巨噬细胞集落刺激因子、单核细胞趋化蛋白、神经毒性因子、超氧化物自由基和髓过氧化物酶表达的诱导。我们还将研究抗体包被的Abeta肽是否对小胶质细胞激活有相同的作用，并确定潜在的Abeta受体在介导这种激活中的相对作用。在特定目标2中，我们将表征尿激酶纤溶酶原激活物受体（uPAR）在小胶质细胞中的表达。该受体在协调炎症细胞的迁移和粘附中起核心作用，用β治疗小胶质细胞可增加uPAR的表达。结合这一点，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诱导和调节。与小胶质细胞uPAR结合的后果将被研究，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β肽与小胶质细胞相互作用后发生的情况。一旦被吞噬，小胶质细胞似乎只有有限的能力随着时间的推移降解β肽。我们建议研究肽是否被降解、络合或经历其他修饰。随着基因阵列和分离技术以及人类遗传数据的可用性，在特定的目标4中，我们建议发现β -小胶质相互作用的新结果。总的来说，这项研究的发现可以扩展我们对阿尔茨海默病大脑中发生的炎症事件的认识。