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原因尚不清楚，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阿尔茨海默氏症大脑中有害的淀粉样β蛋白聚集体的积聚。淀粉样β蛋白通常被大脑中称为小胶质细胞的特殊细胞移除。然而，这些聚集体的去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，设计用于一端捕获淀粉样β蛋白，另一端与小胶质细胞MerTK受体结合。MerTK受体激活一条非炎症性吞噬途径，该途径具有清除淀粉样β蛋白的优势，而不会引发有害因子的产生。如果成功，这项工作可能会对阿尔茨海默氏症和可能的其他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，以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淀粉样β蛋白的清除从炎症途径转移到非炎症吞噬途径。我们已经设计出能够隔离和引导低聚体和纤维状淀粉样β蛋白清除的杂交蛋白。在目标1中，我们将描述该杂交体对MerTK的依赖性、特异性、免疫原性、稳定性和结合动力学。在目标2中，我们将在APP/PS1和3xTg小鼠模型上测试混合制剂是否可以防止AD的进展。在目标3中，我们将确定杂交介导的淀粉样β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.