Clearance and In Vivo Detection of Tau Pathology

Tau 病理学的清除和体内检测

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

在小鼠研究中，针对阿尔茨海默病 (AD) 中淀粉样蛋白 B (AB) 肽的免疫疗法始终能够实现 AB 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，但该试验得出了有希望的初步结果。这些包括减少 AB 负担和认知稳定。目前正在对该方法进行完善，并且多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，其与痴呆程度密切相关。 AD 大脑和小鼠模型的组织学分析表明 AB 和 tau 病理学可能具有协同作用。因此，同时针对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 蛋白聚集，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研究结果表明，用磷酸 tau 衍生物进行免疫可以减少大脑中 tau 蛋白的聚集，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性 tau 蛋白结合。具体目标1是提高针对病理性tau构象异构体主动免疫的治疗效果，阐明其机制并确定该方法是否可以逆转tau病理。 Tangle 模型（P301L 和 htau）将在病理发生之前或之后用 tau 衍生物进行免疫。将评估免疫反应、行为、tau 生物化学和组织学以及相关病理学。同时，将在 1) 体内缠结小鼠中研究抗体介导的清除机制； 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 蛋白聚集体及其清除率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。纵向研究将在接受最有效免疫原和对照的缠结小鼠中进行。 MEMRI 是一种新颖的非侵入性技术，用于对神经活动进行成像，尚未在缠结模型中使用。我们的初步数据显示，与正常对照相比，年轻和年老 P301L 小鼠的锰摄取量分别增加和减少（36% 差异，p<0.001）。 MEMRI 应阐明 tau 聚集体对神经元功能的影响，并可能允许对针对病理性 tau 聚集体的治疗方法进行快速体内评估，这可能会大大缩短这些实验的时间。