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

摘要 慢性炎症病理是脑损伤的主要来源，观察到 唐氏综合征(DS)。尽管这些疾病的确切病因通常是未知的， 过度的白细胞外渗是组织损伤/炎症的重要因素 我们最近的数据显示，血浆蛋白Reelin在这一过程中发挥了突出的作用。 此外，我们现在已经证明，使用抗Reelin单抗，有可能 耗尽血浆中的Reelin，从而显著减少广泛的血管 黏附分子的表达。因此，与目前耗尽个体的方法相比， 黏附分子或免疫受体，我们的抗Reelin方法是系统的 下调血管内皮细胞上所有主要的炎症驱动的黏附蛋白。 本提案的目的是通过1)验证Reelin在DS中的作用 抗Reelin抗体对慢性炎症环境的治疗作用 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.