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大量研究试图阻止淀粉样蛋白的形成和沉积，但针对神经原纤维缠结的形成或其他tau病理的治疗进展很少。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tau积累的有效手段。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，并且在外周给药后抗体显著渗透到神经元中的可能性似乎很小。然而，至少有一些针对tau的单克隆抗体在至少两种不同的tau转基因小鼠系中似乎非常有效地预防病理发展。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牛头病的人身上进行测试之前，需要解决这些问题，其中最重要的是有效性所需抗体的性质。我们提出了一种针对tau的单克隆抗体的分类，根据病理tau聚集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物种的本质

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.