A Mouse Model of Tau Pathology in AD and Other Dementias

描述（由申请人提供）：虽然在小鼠模型和人类患者中已经有许多研究试图预防淀粉样蛋白形成和沉积，但在靶向神经元缠结或其他tau病变的形成方面几乎没有治疗进展。来自我们实验室和其他一些实验室的初步数据强烈表明，免疫疗法可以是预防tau转基因小鼠中tau积累发展的有效手段。这是一个非常令人惊讶的结论，因为tau病理学已被视为细胞内事件，并且外周施用后抗体显著渗透到神经元中的可能性似乎很小。然而，至少一些针对tau的单克隆抗体似乎在预防至少两种不同的tau转基因小鼠系中的病理发展方面非常有效。这种有效性的证据提出了许多问题，在这种方法可以在患有tau蛋白病的人类中进行测试之前，需要解决这些问题，其中最重要的是有效性所需的抗体的性质。我们提出了一种针对tau的单克隆抗体的分类，该分类基于对病理性tau聚集体的特异性将可用抗体分为四组，并将测试所有四组的代表性成员。这项工作也将揭示tau物种的性质， 免疫治疗的目标。在这一点上，甚至还不清楚靶向tau蛋白是否对治疗成功至关重要，并且使用非特异性小鼠IgG的系统研究是必不可少的。 我们已经鉴定了两种抗体（MC1和PHF1），其已经证明在预防小鼠中tau病理学的发展中的功效。广泛的研究已经在进行中，试图确定这两种抗体的作用机制。有争议的说法，有显着的抗体渗透到中枢神经系统神经元在小鼠模型中，将在两个小鼠模型和野生型和转基因小鼠培养的神经元进行深入研究。新的数据显示，tau蛋白从培养的神经元和其他转染tau蛋白的细胞系中积极释放，这表明抗体可能证明有效的新机制。我们将研究三种机制，这些机制被提出来解释tau免疫疗法的疗效。

DESCRIPTION (provided by applicant): While there have been numerous studies in both mouse models and in human patients attempting to prevent amyloid formation and deposition, there have been few therapeutic advances in targeting the formation of neurofibrillary tangles or other tau pathologies. Preliminary data from our lab and from a few others have strongly suggested that immunotherapy can be an effective means of prevention of development of tau accumulation in tau transgenic mice. This is a very surprising conclusion, as tau pathology has been seen as an intracellular event, and the likelihood of significant penetration of antibodies into neurons after peripheral administration appeared to be remote. However, at least some monoclonal antibodies to tau appear to be very effective at prevention of development of pathology in at least two different tau transgenic mouse lines. This evidence for efficacy raises many questions that will need to be addressed before this approach can be tested in humans with tauopathies, not the least of which is the nature of the antibody required for efficacy. We propose a classification of monoclonal antibodies to tau that divides available antibodies into four groups based on specificity for pathological tau aggregates, and will test representative members of all four groups. This work will also shed light on the nature of the tau species that is the target of immunotherapy. At this point, it is not even clear if targeting tau is essential for therapeutic success, and systematic studies with non-specific mouse IgG are essential. We have already identified two antibodies (MC1 and PHF1) that have demonstrated efficacy in prevention of development of tau pathology in mice. Extensive studies are already underway to attempt to determine the mechanism of action of these two antibodies. The controversial claim that there is significant penetration of antibodies into CNS neurons in mouse models will be intensively investigated in both mouse models and in cultured neurons from wild type and transgenic mice. New data showing that tau is actively released from cultured neurons and from other cell lines transfected with tau suggests new mechanisms by which antibodies might prove efficacious. We will examine three mechanisms which have been proposed to explain the efficacy of tau immunotherapy.