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（由申请方提供）：β-淀粉样蛋白沉积物中Abeta蛋白的过度积累是阿尔茨海默病（AD）的标志性事件。近年来，增强β-淀粉样蛋白清除的一些最有前途的治疗策略涉及使用抗Abeta抗体。在AD的转基因动物模型中，β-淀粉样蛋白沉积可以通过外源性抗A β抗体的外周输注（被动）或通过合成A β肽免疫诱导的自身免疫（主动）来抑制。不幸的是，后一种方法与涉及人类CNS脉管系统炎症的潜在致命并发症相关。虽然迄今为止的实验已经使用未修饰的单体Abeta来测试自身免疫性，但AD脑中高达40%的Abeta库由低分子量寡聚交联β-淀粉样蛋白种类（CAPS）组成。此外，许多证据表明可溶性CAPS是AD的主要神经毒性剂。我们最近报道，虽然AD和非痴呆对照受试者血浆中单体Abeta的自身抗体水平相似，但AD患者中CAPS的自身抗体显著降低。此外，AD的发病年龄与CAPS的血浆免疫反应性相关。基于这些发现，我们假设靶向CAPS的Abeta自身抗体的子库通常可以提供对AD发病机制的天然防御，但在AD患者中被耗尽。因此，补充抗CAPS抗体的水平可以潜在地为AD提供治疗益处。在拟议的研究中，我们计划a）鉴定具有最高神经毒性潜力的CAPS，B）使用重组噬菌体展示系统选择对最具神经毒性的CAPS特异性的单链片段可变抗体（scFv），以从超过10^12个人源抗体的载体文库中鉴定CAPS特异性免疫反应性scFv，以及，c）测试抗CAPS scFv抗体在皮质神经元的原代培养物中减弱CAPS神经毒性的活性。我们认为，靶向可溶性CAPS与人源性抗体可能有明显的优势，比以前的疫苗为基础的AD治疗策略，采用更通用的抗-Abeta抗体。最后，关于被动免疫疗法，通过特异性靶向与AD病理学最相关的Abeta种类，可以规定较低的抗Abeta抗体滴度，从而减弱与炎症相关的潜在副作用。