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直导致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叫停，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A？负担和稳定认知。对这种方法的改进目前正在进行中，几家公司已经启动了更多的临床试验。AD的另一个重要靶点是神经原纤维缠结，主要由过度磷酸化的tau蛋白组成，它与痴呆症的程度密切相关。在AD脑和小鼠模型中的组织学分析表明，A和tau的病理可能是协同作用的。因此，同时针对这两种病理可能会更有效。此外，免疫疗法不会减少AD或小鼠模型中的tau聚集体，这表明了开发单独的缠结靶向疗法的重要性。我们在两个缠结小鼠模型上的发现表明，用磷酸化tau衍生物免疫减少了大脑中聚集的tau，并减缓了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性tau结合。具体目的1是提高针对病理性tau构象的主动免疫的治疗效果，阐明其作用机制，并确定该方法是否能逆转tau的病理变化。Tangle模型(P301L和htau)将在病理发生之前或之后用tau衍生物免疫。将对免疫反应、行为、tau生化和组织学以及相关病理进行评估。同时，将在1)体内缠绕小鼠和2)脑片缠绕模型中研究抗体介导的清除机制。这些研究应该明确哪种类型的tau免疫疗法可能是安全和有效的，并应该确定一种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的神经活动，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免疫原的缠绕小鼠和对照小鼠身上进行。MEMRI是一种新的非侵入性成像神经活动的技术，尚未在缠绕模型中使用。我们的初步数据显示，与正常对照组相比，年轻和老年P301L小鼠的锰摄取量分别增加和减少(差异36%，p&lt；0.001)。MEMRI应该阐明tau聚集体对神经元功能的影响，并可以在体内快速评估针对病理性tau聚集体的治疗方法，这可能会大大缩短这些实验。公共卫生相关性目前还没有有效的治疗阿尔茨海默病的方法。这项建议的目的是开发针对神经原纤维缠结和/或其病理tau前体的进一步治疗，这是该病的主要特征之一。此外，我们建议开发一种体内成像技术，以阐明tau聚集体的神经毒性效应，这种方法可能被用于监测活体动物的治疗，并可能在未来诊断这种疾病。

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.