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

摘要 慢性炎性病理学代表了在脑损伤中观察到的脑损伤的主要来源。 唐氏综合征（Down's Syndrome，DS）虽然这些疾病的确切病因往往是未知的， 过多的白细胞外渗是组织损伤/炎症的主要原因 我们最近的数据表明，血浆蛋白Reelin在这一过程中起着重要作用。 此外，我们现在已经证明，使用抗Reelin单克隆抗体， 消耗血浆中的Reelin，这导致大范围的血管炎的显著减少。 粘附分子表达。因此，与当前消耗个体能量的方法相比， 粘附分子或免疫受体，我们的抗Reelin方法系统地 下调血管内皮上所有主要炎症驱动的粘附蛋白。 本提案的目的是通过1）验证 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.