Effect of APP copy number variants in Alzheimer's disease and and Down Syndrome on Reelin expression and function

摘要 慢性炎症病理学是观察到的大脑损伤的主要来源。 唐氏综合症（DS）。尽管这些疾病的确切病因通常未知， 过度的白细胞外渗是组织损伤/炎症的重要原因 我们最近的数据显示血浆蛋白 Reelin 在此过程中发挥着重要作用。 此外，我们现在已经证明，使用抗 Reelin 单克隆抗体是可能的 消耗 Reelin 的血浆，从而导致大范围的血管显着减少 粘附分子的表达。因此，与目前消耗个人资源的方法相比， 粘附分子或免疫受体，我们系统地抗 Reelin 方法 下调血管内皮上所有主要炎症驱动的粘附蛋白。 该提案的目的是通过 1) 验证 Reelin 在 DS 中的作用 使用抗 Reelin 抗体减轻慢性炎症环境的治疗潜力 DS 小鼠模型和 2) 鉴定用于未来治疗的高亲和力 Reelin 抗体 发展。

Abstract Chronic inflammatory pathology represents a major source of damage to the brain observed in Down’s syndrome (DS). Although the precise etiology of these diseases is often unknown, excessive leukocyte extravasation is a substantial contributor to the tissue damage/inflammation and our recent data show a prominent role of the plasma protein, Reelin in this process. Furthermore, we have now shown that it is possible, using anti-Reelin monoclonal antibodies, to deplete the plasma of Reelin, which results in a significant reduction of a wide range of vascular adhesion molecule expression. Thus, in contrast to the current methods of depleting individual adhesion molecules or immune receptors, our anti-Reelin approach systematically downregulates all major inflammation-driven adhesion proteins on the vascular endothelium. The purpose of this proposal is to demonstrate the role of Reelin in DS by 1) validating the therapeutic potential of mitigating chronic inflammatory milieu with an anti-Reelin antibody in an DS mouse model and 2) identifying high affinity Reelin antibodies for future therapeutic development.