Phagocytosis 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、语言和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，目前还没有治愈方法。阿尔茨海默氏症的主要疾病特征之一是有害的淀粉样蛋白聚集在阿尔茨海默氏症患者的大脑中。淀粉样蛋白通常会被大脑中一种叫做小胶质细胞的特殊细胞移除。然而，这些聚集体的移除会导致炎症途径的激活，最终导致脑细胞死亡。利用基因工程，我们创造了一种新型的“分子桥”，这是一种杂交蛋白，其一端捕获淀粉样蛋白，另一端与小胶质MerTK受体结合。MerTK受体激活非炎性吞噬途径，其优点是在不引起有害因子产生的情况下清除β淀粉样蛋白。如果成功，这项工作可能会对阿尔茨海默氏症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。我们设计了杂交蛋白，可以隔离和指导低聚和纤维状淀粉样蛋白的清除。在Aim 1中，我们将对MerTK依赖性、特异性、免疫原性、稳定性和结合动力学进行表征。在Aim 2中，我们将在APP/PS1和3XTg小鼠模型中测试Hybrid是否可以阻止AD的进展。在Aim 3中，我们将确定混合介导的β淀粉样蛋白清除的分子机制。

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.