Phagocytosis of Amyloid Beta

β淀粉样蛋白的吞噬作用

• 批准号: 10170377
• 负责人: Nora Blanca Caberoy
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170377
• 关键词: 3xTg-AD mouse; APP-PS1; Abeta clearance; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-Protein; Binding; Brain; Cell Death; Cells; Centers of Research Excellence; Cessation of life; Cognition; Complex; Dependence; Disease; Engineering; Excision; Genetic Engineering; Goals; Hybrids; Impairment; Inflammatory; Kinetics; Language; Mediating; Memory; Metabolic; Microglia; Molecular; Neurodegenerative Disorders; Nevada; Pathway interactions; Phagocytes; Phagocytosis; Production; Specificity; Testing; Visual; Work; brain cell; design; hybrid protein; immunogenicity; mouse model; novel therapeutic intervention; personalized medicine; prevent; protein aggregation; receptor; skills

Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by impairment in memory, complex cognition, language, and visual or spatial skills. The exact cause for Alzheimer’s is poorly understood and currently there is no cure. One of the major disease hallmarks of Alzheimer’s is the buildup of harmful amyloid beta protein aggregates in the Alzheimer’s brain. Amyloid betas are normally removed by specialized cells in the brain called microglia. However, the removal of these aggregates leads to activation of the inflammatory pathway that eventually results to death of the brain cells. Using genetic engineering, we have created a new type of “molecular bridge”, a hybrid protein that is designed to capture amyloid beta on one end and to bind to microglial MerTK receptor on the other end. The MerTK receptor activates a non-inflammatory phagocytic pathway which would have the advantage of clearing amyloid beta without eliciting the production of deleterious factors. If successful, this work could have a significant impact on the treatment for Alzheimer’s and likely other neurodegenerative disorders. Our long-term goal is to develop a novel therapeutic strategy for clearing deleterious metabolic products to prevent Alzheimer’s disease. Our immediate objective is to divert the clearance of amyloid beta from the inflammatory pathway to the non-inflammatory phagocytosis pathway. We have engineered hybrid proteins that can sequester and direct the clearance of both oligomeric and fibrillar forms of amyloid beta. In Aim 1, we will characterize the Hybrid for MerTK dependency, specificity, immunogenicity, stability, and binding kinetics. In Aim 2, we will test whether the Hybrid can prevent progression of AD in APP/PS1 and 3XTg mouse models. In Aim 3, we will determine the molecular mechanism of Hybrid-mediated clearance of amyloid beta.

阿尔茨海默病是一种进行性神经退行性疾病，其特征是记忆、复杂认知、语言以及视觉或空间技能受损。阿尔茨海默氏症的确切病因尚不清楚，目前尚无治愈方法。阿尔茨海默氏症的主要疾病特征之一是有害的淀粉样β蛋白在阿尔茨海默氏症大脑中聚集。 β 淀粉样蛋白通常被大脑中称为小胶质细胞的特殊细胞去除。然而，去除这些聚集物会导致炎症途径激活，最终导致脑细胞死亡。利用基因工程，我们创建了一种新型“分子桥”，这是一种混合蛋白，旨在一端捕获β淀粉样蛋白，另一端与小胶质细胞MerTK受体结合。 MerTK 受体激活非炎症吞噬途径，该途径具有清除β淀粉样蛋白而不引起有害因子产生的优点。如果成功，这项工作可能会对阿尔茨海默病和其他可能的神经退行性疾病的治疗产生重大影响。我们的长期目标是开发一种新的治疗策略来清除有害的代谢产物以预防阿尔茨海默病。我们的直接目标是将β淀粉样蛋白的清除从炎症途径转移到非炎症吞噬途径。我们设计了混合蛋白，可以隔离并指导清除寡聚体和纤维状β淀粉样蛋白。在目标 1 中，我们将表征杂交体的 MerTK 依赖性、特异性、免疫原性、稳定性和结合动力学。在目标 2 中，我们将测试 Hybrid 是否可以阻止 APP/PS1 和 3XTg 小鼠模型中 AD 的进展。在目标 3 中，我们将确定 Hybrid 介导的 β 淀粉样蛋白清除的分子机制。