Immunotherapy in Alzheimer's Disease Animal Models Using Tau Recombinant Antibodies

项目总结/摘要 在过去的几年里，越来越多的证据支持细胞外tau蛋白的存在， tau蛋白种类的跨细胞传播作为阿尔茨海默氏症的起始和进展的机制 疾病在这种情况下，使用抗体靶向tau病理学似乎是一种适当的方法， 阿尔茨海默病（AD）模型中的神经元缠结。已经产生了大量的数据 通过不同的实验室显示在使用tau的转基因动物模型中有效减少tau病理学 单克隆抗体，根据所靶向的表位具有不同程度的成功。然而，尽管如此， tau抗体作为tau病理学治疗的机制仍不清楚。为了解决这个 我们将使用由重链和轻链可变区组成的工程抗体 通过短接头（scFv）连接，保留亲本抗体的表位特异性和亲和力。工作 本申请中提出的方法设计为使用病毒载体（AAV）携带的tau scFv， 靶向神经元或星形胶质细胞。我们将对应于以下的scFv克隆到病毒载体中： 先前在被动免疫实验中测试的不同tau抗体。这些工程工具将 首先在体外使用，以解决减少tau蛋白的最有效策略是否 磷酸化/聚集将靶向从细胞外环境或从神经元内环境起作用的tau。 车厢此外，我们将测试是否通过提供重组抗体的长期释放， 直接在小鼠脑实质中，无论是通过神经元内产生还是通过细胞外暴露，我们可以 定义这些抗体发挥其治疗作用的机制，并开发一种 在转基因动物模型和潜在的人类中减少tau聚集体的有效策略。

PROJECT SUMMARY/ABSTRACT Over the past few years, increasing evidence has supported the existence of extracellular tau and the concept of transcellular propagation of tau species as a mechanism for the initiation and progression of Alzheimer's disease. In this context, using antibodies to target tau pathology appeared an appropriate approach to clear neurofibrillary tangles in Alzheimer's disease (AD) models. A conspicuous amount of data has been produced by different laboratories showing efficient reduction of tau pathology in transgenic animal models using tau monoclonal antibodies, with a different degree of success according to the epitopes targeted. Nevertheless, the mechanism by which tau antibodies function as treatments for tau pathology is still unclear. To address this point, we will employ engineered antibodies composed of the variable regions of the heavy and light chains joined by a short linker (scFv), preserving the epitope specificity and affinity of the parent antibodies. The work proposed in this application is designed to use tau scFvs carried by viral vectors (AAV) in order to specifically target neurons or astrocytes in vitro and in vivo. We will clone into viral vectors the scFvs corresponding to different tau antibodies previously tested in passive immunization experiments. These engineered tools will be used first in vitro in order to address the question whether the most efficient strategy to reduce tau phosphorylation/aggregation will be to target tau acting from the extracellular milieu or from the intraneuronal compartment. Furthermore, we will be testing if by providing a chronic release of recombinant antibodies directly in the mice brain parenchyma, either by intraneuronal production or by extracellular exposure, we can define the mechanism by which these antibodies exert their therapeutic effects as well as developing an efficient strategy to reduce tau aggregates in transgenic animal models and potentially in humans.