scFv-based Abeta Oligomer Targeting in 3xTg-AD Mice

描述(申请人提供)：阿尔茨海默病(AD)是一种进行性痴呆的疾病，其特征是致病多肽在大脑中积聚，主要由淀粉样β蛋白(AB)组成，是淀粉样前体蛋白(APP)的衍生物。AB1-42是主要的胞外形式，由2-和3-分泌酶两种内切酶裂解APP而产生，并组装成寡聚体，其中一些被认为损害了突触功能。我们的实验室感兴趣的是了解启动或维持AD发病的这种时间和空间进展的早期机制，并利用对这些机制的理解来获得新的治疗方法。治疗阿尔茨海默病的一种策略是消耗实质空间内的抗体，并阻止可能的破坏性寡聚体的形成。有几个小组已经成功地通过主动或被动的方式引入抗体，尽管许多小组引起了令人不快的免疫事件。在所追求的方法中，我们试图将重组病毒载体输送到AD脑中，以表达针对抗体寡聚体的人源单链片段可变抗体(ScFv)，目的是促进其清除，防止突触功能障碍和神经元毒性。我们假设，使用针对寡聚型抗体的单链抗体的基于基因的被动免疫将防止抗体产生的突触毒性，并将减少下游的病理事件，包括淀粉样斑块、神经纤维缠结形成以及对神经元活性的相关影响。表达工程抗体的重组腺相关病毒(RAAV)载体将在神经元内抗体(2个月大)首次出现之前被注射到3xTg-AD小鼠，这是一种同时发生淀粉样蛋白和tau病理的AD小鼠模型。这项工作将提供对寡聚体抗体参与早期AD致病事件的时间和空间进展的机械性洞察，并可能导致设计用于早期干预的新的抗抗体疗法的发展。公共卫生相关性：阿尔茨海默病(AD)是一种潜伏的神经退行性疾病，具有重大的社会和经济影响。针对目前被认为是疾病早期介导者的疾病靶点的更精细疗法的发展，以及它们在最先进的动物模型中的详细评估，将带来一种新的疗法类别，潜在的不仅仅是改善症状，而且真正改变疾病的进程。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressively dementing disorder characterized by the accumulation in the brain of pathogenic peptides largely comprised of amyloid-beta peptide (Ab), a derivative of the amyloid precursor protein (APP). Ab1-42, the predominant extracellular form, arises from cleavage of APP by two endoproteases, the 2- and 3- secretases, and undergoes assembly into oligomeric forms some of which are postulated to compromise synaptic function. Our laboratory is interested in understanding the early mechanisms that initiate or perpetuate this temporal and spatial progression of AD pathogenesis, and in exploiting an understanding of these mechanisms to derive novel therapeutics. One strategy to treat AD is to deplete the Ab within the parenchymal space and preclude formation of the putative damaging oligomeric forms. Several groups have been successful by introducing antibodies through either active or passive means, although many have incurred untoward immunological events. Among the approaches pursued we seek to deliver to the AD brain recombinant viral vectors that will express a human single chain fragment variable (scFv) antibody directed against Ab oligomeric forms with the goal of facilitating its clearance and preventing synaptic dysfunction and neuronal toxicity. We hypothesize that gene-based passive immunization using single-chain antibodies directed against oligomeric forms of Ab will prevent Ab-engendered synaptotoxicity and will diminish the downstream pathological events that include amyloid plaques, neurofibrillary tangle formation, and associated effects on neuronal viability. Recombinant adeno-associated virus (rAAV) vectors expressing the engineered antibodies will be administered to 3xTg-AD mice, a mouse model of AD that develops both amyloid and tau pathology, prior to the initial appearance of intraneuronal Ab (2 months of age). This work will provide mechanistic insight into the involvement of oligomeric Ab in the temporal and spatial progression of early AD pathogenic events and will potentially lead to the development of new anti-Ab therapeutics designed for early-stage intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is an insidious neurodegenerative disorder that wields significant societal and economic impact. The development of more refined therapeutics directed at disease targets presently believed to be early mediators of the disease and their detailed assessment in state-of-the-art animal models will usher in a new class of therapeutics with the potential to be more than symptom-ameliorating, but truly disease course-modifying.