Mechanism of Abeta Sequestration

描述（由申请人提供）：阿尔茨海默病（AD）是一种与记忆功能障碍相关的神经退行性疾病。在家族性AD患者中已经发现了多个基因的病理突变，并产生了携带病理基因的转基因小鼠。淀粉样变性转基因模型的产生极大地促进了旨在降低脑淀粉样蛋白（Abeta）负荷的治疗方法的发展。其中一种方法被称为“免疫接种”。免疫诱导（或被动给予）抗β抗体已被证明可增强转基因小鼠大脑中的小胶质细胞吞噬并减少β负荷。值得注意的是，免疫也逆转了与β相关的记忆功能障碍。伴随CNS β减少的是我们和其他人同时观察到免疫后血浆β水平显著升高。根据这一观察结果，我们设计了一种新的方法来改变大脑的β负荷，该方法在初步研究中被证明是有效的。在人类主动免疫临床试验中，大约6%的患者发现严重的脑部炎症后，终止了Abeta疫苗方法。脑炎症副作用的原因尚不清楚，但很可能是免疫调节引起的。虽然疫苗治疗的第一个临床试验终止了，但后续报告令人鼓舞。隔离方法不调节免疫反应；因此，it疗法在药物开发上具有更高的灵活性，并且基于隔离方法的药物副作用更小。此外，当这种方法转化为临床应用时，血浆β升高可能是一种生物标志物。在本研究中，我们将探讨Abeta的隔离机制，确定最佳的分子特性和可药物靶点，为未来的药理治疗开发提供依据。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Pathological mutations in familial AD patients have been identified in several genes, and transgenic mice carrying pathological genes have been generated. The generation of transgenic models of amyloidosis has significantly aided progress in the development of therapeutic approaches designed to lower brain amyloid beta (Abeta) load. One of these approaches is called "immunization". Immunologically provoked (or passively administered) antibodies against Abeta have been shown to enhance microglial phagocytosis and reduce Abeta load in the brains of transgenic mice. Significantly, immunization also reversed Abeta associated memory dysfunction. Concomitant with reduced CNS Abeta is the simultaneous observation by us and others that plasma Abeta levels are significantly elevated following immunization. As a result of this observation, we have devised a new methodology to alter brain Abeta load, which has proved to be effective in preliminary studies. In the human active immunization clinical trial, Abeta vaccine approach was terminated after severe brain inflammation was found approximately in 6% of patients. The cause of brain inflammatory side effects is not clear yet, but it is most likely due to immune modulation. Although the first clinical trial of vaccine therapy was terminated, follow up reports are encouraging. Sequestration approach does not modulate immune reaction; therefore, it therapy has higher flexibility in drug development, and drugs based on sequestration approaches have less side effects. In addition, plasma Abeta elevation is a possible biomarker when this approach translates to clinical use. In this study, we will investigate the mechanism of Abeta sequestration mechanism and identify optimal molecular property and drugable target for future development of pharmacological therapy.