Clearance and In Vivo Detection of Tau Pathology

描述（由申请人提供）：针对阿尔茨海默病（AD）中淀粉样蛋白- (A)肽的免疫疗法在小鼠研究中一致导致A -清除和认知改善。由于在一小部分患者中观察到脑炎，使用这种方法的临床试验被停止，但从这项试验中出现了有希望的初步发现。这些措施包括减轻大脑负担和保持认知稳定。目前正在对这种方法进行改进，几家公司已经启动了额外的临床试验。阿尔茨海默病的另一个重要靶点是神经原纤维缠结，它主要由过度磷酸化的tau蛋白组成，与痴呆症的程度密切相关。AD大脑和小鼠模型的组织学分析表明，A¿和tau病理可能是协同的。因此，同时针对这两种病理可能更有效。此外，A¿免疫疗法不会降低AD或小鼠模型中的tau聚集，这表明开发单独的缠结靶向治疗的重要性。我们在两个缠结小鼠模型中的研究结果表明，用磷酸化tau衍生物免疫可减少大脑中聚集的tau蛋白，并减缓缠结相关行为表型的进展。这些抗体进入大脑并与神经元内的病理tau蛋白结合。特异性目的1是提高主动免疫对病理性tau构象的治疗效果，阐明其机制，并确定该方法是否可以逆转tau病理。缠结模型（P301L和htau）将在病理发作之前或之后用tau衍生物免疫。免疫反应，行为，tau生物化学和组织学以及相关病理将被评估。同时，抗体介导的清除机制将在1)缠结小鼠体内进行研究；2)脑切片缠结模型。这些研究应阐明哪种类型的tau免疫疗法可能是安全有效的，并应确定用于临床试验的免疫原。具体目标2是确定tau聚集体及其清除如何影响体内神经活动，并利用锰增强磁共振成像（MEMRI）监测治疗效果。纵向研究将在接受最有效的免疫原和对照的缠结小鼠中进行。MEMRI是一种新的非侵入性神经活动成像技术，尚未用于缠结模型。我们的初步数据显示，与正常对照相比，年轻和年老P301L小鼠的锰摄取分别增加和减少（差异36%，p<0.001）。MEMRI应阐明tau聚集体对神经元功能的影响，并可能允许针对病理性tau聚集体的治疗方法的快速体内评估，这可能大大缩短这些实验。目前还没有有效的治疗阿尔茨海默病的方法。该建议的目的是开发针对神经原纤维缠结和/或其病理性tau前体的进一步治疗，这是该疾病的主要标志之一。此外，我们建议开发一种体内成像技术，以阐明tau聚集体的神经毒性作用，这种方法可能用于监测活体动物的治疗，并可能在未来诊断疾病。

DESCRIPTION (provided by applicant): Immunotherapies that target the amyloid-¿ (A¿) peptide in Alzheimer's disease (AD) have consistently resulted in A¿ clearance and cognitive improvements in mouse studies. Clinical trials using this approach were halted because of encephalitis observed in a small subset of patients but promising preliminary findings have emerged from this trial. These include reduction in A¿ burden and cognitive stabilization. Refinement of this approach is currently underway, and additional clinical trials have been initiated by several companies. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. Histological analysis in AD brains and mouse models indicate that A¿ and tau pathologies are likely synergistic. Hence, targeting both pathologies at the same time may be more effective. Also, A¿ immunotherapy does not reduce tau aggregates in AD or mouse models, showing the importance of developing a separate tangle-targeting therapy. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. Specific Aim 1 is to improve the therapeutic effect of active immunization against pathological tau conformers, clarify its mechanism and to determine if this approach can reverse tau pathology. Tangle models (P301L and htau) will be immunized with tau derivatives prior to or following the onset of pathology. Immune response, behavior, tau biochemistry and histology as well as associated pathology will be assessed. Concurrently, the mechanism of antibody-mediated clearance will be studied in 1) tangle mice in vivo; and 2) a brain slice tangle model. These studies should clarify which type of tau immunotherapy is likely to be safe and effective, and should identify an immunogen for clinical trials. Specific Aim 2 is to determine how tau aggregates and their clearance influence neural activity in vivo, and to monitor treatment efficacy with manganese-enhanced magnetic resonance imaging (MEMRI). Longitudinal study will be performed in tangle mice that receive the most effective immunogen and controls. MEMRI is a novel non-invasive technique to image neural activity that has not been used in tangle models. Our preliminary data shows an increased and decreased manganese uptake in young and old P301L mice, respectively (36% difference, p<0.001), compared to normal controls. MEMRI should clarify the effects of tau aggregates on neuronal function and may allow a rapid in vivo evaluation of therapeutic approaches targeting pathological tau aggregates, which may substantially shorten these experiments. PUBLIC HEALTH RELEVANCE There is currently no effective treatment for Alzheimer's disease. The aim of this proposal is to develop further therapy that targets neurofibrillary tangles and/or their pathological tau precursors, which are one of the major hallmarks of the disease. Furthermore, we propose to develop an in vivo imaging technique that will clarify the neurotoxic effects of tau aggregates, and this approach may be used to monitor therapy in live animals and possibly to diagnose the disease in the future.