Clearance and In Vivo Detection of Tau Pathology

Tau 病理学的清除和体内检测

• 批准号: 8673411
• 负责人: Einar M Sigurdsson
• 金额: $ 32.94万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673411
• 关键词: Active Immunization; Affect; Alzheimer' s Disease; Amyloid; Animals; Antibodies; Antigens; Autopsy; Behavior; Behavioral; Binding; Biochemistry; Brain; Brain imaging; Calcium Channel; Cerebrum; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Dementia; Detection; Disease; Dissociation; Encephalitis; Epitopes; Future; Hippocampus (Brain); Histology; Human; Image; Imaging Techniques; Immune response; Immunization; Immunotherapy; Ions; Knockout Mice; Lead; Life; Light; Longitudinal Studies; Magnetic Resonance Imaging; Manganese; Mediating; Memory; Memory Loss; Methods; Modeling; Monitor; Mus; Neurofibrillary Tangles; Neurons; Parkinson Disease; Participant; Pathological Staging; Pathology; Pathway interactions; Patients; Phenotype; Publishing; Reporting; Signal Transduction; Slice; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Vaccination; Weight; alpha synuclein; base; conformer; disease diagnosis; effective therapy; extracellular; hyperphosphorylated tau; immunoregulation; improved; in vivo; mouse model; neuron loss; neurotoxic; novel; peptide B; relating to nervous system; research study; tau Proteins; tau aggregation; tau-1; therapeutic evaluation; uptake; voltage

Immunotherapies that target the amyloid-B (AB) peptide in Alzheimer's disease (AD) have consistently resulted in AB 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 AB 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 AB and tau pathologies are likely synergistic. Hence, targeting both pathologies at the same time may be more effective. Also, AB 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.

针对阿尔茨海默病（AD）中淀粉样蛋白B（AB）肽的免疫疗法在小鼠研究中一直导致AB清除和认知改善。使用这种方法的临床试验由于在一小部分患者中观察到脑炎而停止，但这项试验已经出现了有希望的初步结果。这些包括AB负担的减少和认知稳定。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。 AD的另一个重要靶点是神经元缠结，主要由过度磷酸化的tau蛋白组成，与痴呆的程度密切相关。AD脑和小鼠模型中的组织学分析表明AB和tau病理可能是协同的。因此，同时靶向两种病理可能更有效。此外，AB免疫疗法不会减少AD或小鼠模型中的tau聚集体，这表明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中的发现表明，用磷酸化tau衍生物免疫减少了大脑中聚集的tau蛋白，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蛋白结合。 具体目的1是提高主动免疫对病理性tau构象异构体的治疗效果，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）将在病理学发作之前或之后用tau衍生物免疫。将评估免疫应答、行为、tau生物化学和组织学以及相关病理学。同时，将在1）缠结小鼠体内和2）脑切片缠结模型中研究抗体介导的清除机制。这些研究应该澄清哪种类型的tau免疫疗法可能是安全有效的，并应该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，并通过锰增强磁共振成像（MEMRI）监测治疗效果。将在接受最有效免疫原的缠结小鼠和对照中进行纵向研究。MEMRI是一种新的非侵入性技术，用于成像神经活动，尚未用于缠结模型。我们的初步数据显示，与正常对照组相比，年轻和老年P301L小鼠的锰摄取分别增加和减少（差异36%，p<0.001）。MEMRI应该澄清tau聚集体对神经元功能的影响，并可能允许快速体内评估靶向病理性tau聚集体的治疗方法，这可能会大大缩短这些实验。