Targeting cross-linked amyloid protein species as a therapy for AD.

靶向交联淀粉样蛋白作为 AD 的治疗方法。

• 批准号: 7076746
• 负责人: ROBERT D MOIR
• 金额: $ 22.31万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076746
• 关键词: Alzheimer' s disease; acquired immunodeficiency; aging; amyloid proteins; animal tissue; autoantibody; autoimmunity; bioassay; crosslink; disease /disorder etiology; high performance liquid chromatography; immune response; molecular site; neurons; neurotoxicology; passive immunization; peptide library; tissue /cell culture

DESCRIPTION (provided by applicant): Excessive accumulation of Abeta protein in beta-amyloid deposits is a hallmark event in Alzheimer's disease (AD). In recent years, some of the most promising therapeutic strategies for potentiating beta-amyloid clearance has involved the use of anti-Abeta antibodies. In transgenic animal models of AD beta-amyloid deposition can be inhibited by either peripheral infusion of exogenous anti-Abeta antibodies (passive) or autoimmunity induced by immunization with synthetic Abeta peptide (active). Unfortunately, the latter approach has been associated with potentially fatal complications involving inflammation of the CNS vasculature in humans. While experiments to date have employed unmodified monomeric Abeta to test for autoimmunity, up to 40 % of the Abeta pool in AD brain consists of low molecular weight oligomeric cross-linked beta-amyloid protein species (CAPS). Moreover, numerous lines of evidence have implicated soluble CAPS as the primary neurotoxic agent in AD. We have recently reported that while levels of autoantibodies to monomeric Abeta are similar in the plasma of AD and non-demented control subjects, autoantibodies to CAPS are significantly reduced in AD patients. In addition, age-at-onset for AD correlates with plasma immunoreactivity to CAPS. Based on these findings, we hypothesize that the sub-pool of Abeta autoantibodies targeted at CAPS may normally provide a natural defense against AD pathogenesis, but are depleted in AD patients. Accordingly, replenishing the level of anti-CAPS antibodies could potentially provide therapeutic benefit for AD. In the proposed study we plan to a) identify CAPS with the highest neurotoxic potential, b) select single-chain fragment variable antibodies (scFvs) specific for the most neurotoxic CAPS using recombinant phage display system to identify CAPS-specific immunoreactive scFvs from a vector library of over 10^12 human derived antibodies, and, c) test anti-CAPS scFv antibodies for activity in attenuating CAPS neurotoxicity in primary cultures of cortical neurons. We posit that targeting soluble CAPS with human derived antibodies may have distinct advantages over previous vaccine-based AD treatment strategies that have employed more generic anti-Abeta antibodies. Finally, with regard to passive immunization therapies, by specifically targeting the Abeta species that are most relevant to AD pathology, lower anti-Abeta antibody titers might be prescribed, thereby attenuating potential side-effects associated with inflammation.

描述（由申请人提供）：β-淀粉样蛋白沉积物中Abeta蛋白的过度积累是阿尔茨海默氏病（AD）的标志性事件。近年来，一些增强β-淀粉样蛋白清除的最有前途的治疗策略涉及使用抗ABETA抗体。在ADβ-淀粉样蛋白沉积的转基因动物模型中，可以通过外围抗Abeta抗体（被动）或通过合成ABETA肽免疫引起的自身免疫性来抑制ADβ-淀粉样蛋白沉积。不幸的是，后一种方法与潜在的致命并发症有关，涉及人类中枢神经系统脉管系统的炎症。迄今为止，实验已采用未修饰的单体ABETA来测试自身免疫性，但AD脑中多达40％的Abeta池由低分子量的低分子量寡聚交联β-淀粉样蛋白（CAPS）组成。此外，许多证据线已将可溶性帽作为AD中的主要神经毒性剂。我们最近报道说，尽管AD和非痴呆对照受试者的血浆中的自身抗体水平相似，但AD患者的自身抗体显着降低。此外，AD的年龄与CAP的血浆免疫反应性相关。根据这些发现，我们假设针对CAPS的ABETA自身抗体的子池通常可以提供针对AD发病机理的自然防御，但在AD患者中会耗尽。因此，补充抗CAP抗体的水平可能有可能为AD提供治疗益处。 In the proposed study we plan to a) identify CAPS with the highest neurotoxic potential, b) select single-chain fragment variable antibodies (scFvs) specific for the most neurotoxic CAPS using recombinant phage display system to identify CAPS-specific immunoreactive scFvs from a vector library of over 10^12 human derived antibodies, and, c) test anti-CAPS scFv antibodies for activity in皮质神经元原发性培养物中的神经毒性减弱。我们认为，使用人类衍生抗体靶向可溶性帽可能比以前基于疫苗的AD治疗策略具有不同的优势，这些抗体采用了更多的抗Abeta抗体。最后，关于被动免疫疗法，通过专门针对与AD病理学最相关的ABETA物种，可能会开处方较低的抗ABETA抗体滴度，从而减轻与炎症相关的潜在副作用。