A Mouse Model of Tau Pathology in AD and Other Dementias

AD 和其他痴呆症中 Tau 蛋白病理学的小鼠模型

• 批准号: 8850752
• 负责人: PETER P DAVIES
• 金额: $ 33.51万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850752
• 关键词: A Mouse; Address; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Antibodies; Antibody Specificity; Astrocytes; Binding; Blood Circulation; Cell Line; Classification; Data; Dementia; Development; Disease; Event; Health; Human; Immunoglobulin G; Immunotherapy; Intercellular Fluid; Light; Microglia; Monoclonal Antibodies; Mus; Nature; Neurofibrillary Tangles; Neurons; Pathology; Patients; Penetration; Peripheral; Prevention; Specificity; Tauopathies; Testing; Therapeutic; Transgenic Mice; Work; amyloid formation; base; efficacy testing; extracellular; human disease; member; mouse model; neurofibrillary tangle formation; prevent; success; tau Proteins; tau aggregation; uptake

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.

描述（由申请人提供）：虽然在小鼠模型和试图预防淀粉样蛋白形成和沉积的人类患者中进行了许多研究，但在靶向靶向神经原纤维缠结或其他TAU病理学的靶向方面几乎没有治疗进展。来自我们实验室和其他一些人的初步数据强烈建议免疫疗法可以预防tau转基因小鼠中tau积累的有效手段。这是一个非常令人惊讶的结论，因为Tau病理学被视为一个细胞内事件，并且在外周施用后，抗体显着渗透到神经元中的可能性似乎是遥远的。但是，至少有一些对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。这种疗效的证据提出了许多问题，这些问题需要在患有陶氏病的人类中进行测试，这需要解决这种方法，其中最不重要的一点是疗效所需的抗体的本质。我们提出了将单克隆抗体分类的TAU，该抗体将可用的抗体基于病理TAU聚集体的特异性将可用的抗体分为四组，并将测试所有四个组的代表成员。这项工作还将阐明tau物种的性质 免疫疗法的靶标。在这一点上，尚不清楚靶向tau是否对于治疗成功至关重要，并且对非特异性小鼠IgG的系统研究至关重要。 我们已经确定了两种抗体（MC1和PHF1），这些抗体在预防小鼠中tau病理学发育方面有效。已经进行了广泛的研究，以确定这两种抗体的作用机理。在小鼠模型和来自野生型和转基因小鼠的培养神经元中，将对小鼠模型中的CNS神经元中的抗体显着渗透到CNS神经元中的有争议的说法。新数据表明，TAU是从培养的神经元中积极释放的，并从带有TAU转染的其他细胞系中提出了抗体可能被证明有效的新机制。我们将研究已提出的三种机制来解释Tau免疫疗法的功效。