A Mouse Model of Tau Pathology in AD and Other Dementias

描述(申请人提供)：虽然在小鼠模型和人类患者中都有许多研究试图防止淀粉样蛋白的形成和沉积，但在针对神经原纤维缠结或其他tau病理的形成方面的治疗进展很少。来自我们实验室和其他一些实验室的初步数据有力地表明，免疫疗法可以有效地防止tau转基因小鼠体内tau的积聚。这是一个非常令人惊讶的结论，因为tau病理一直被视为细胞内事件，而且在外周给药后抗体显著渗透到神经元的可能性似乎很小。然而，在至少两个不同的tau转基因小鼠系中，至少有一些抗tau的单抗似乎在防止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甲状旁腺疾病的人类身上进行测试之前，需要解决许多问题，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的单抗的分类，根据对病理性tau聚集体的特异性，将可用的抗体分为四组，并将测试所有四组的代表性成员。这项工作还将揭示牛属物种的性质，即 免疫治疗的靶点。在这一点上，甚至不清楚靶向tau是否是治疗成功的关键，对非特异性小鼠免疫球蛋白进行系统研究是必要的。我们已经确定了两种抗体(MC1和PHF1)，它们已经证明了在预防小鼠tau病理发展方面的有效性。已经在进行广泛的研究，试图确定这两种抗体的作用机制。有争议的说法是，抗体在小鼠模型中显著渗透到中枢神经系统神经元中，这一说法将在两个小鼠模型以及野生型和转基因小鼠的培养神经元中进行深入研究。新的数据显示，从培养的神经元和其他转染了tau的细胞株中，tau被活跃地释放出来，这表明抗体可能被证明是有效的新机制。我们将考察三种已提出的解释tau免疫疗法疗效的机制。

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.