Novel Acetylated Tau Immunotherapy for Alzheimer's disease

治疗阿尔茨海默病的新型乙酰化 Tau 免疫疗法

• 批准号: 10428347
• 负责人: Miles Richard Bryan
• 金额: $ 7.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-27 至 2024-04-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428347
• 关键词: Acetylation; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnostic; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid beta-Protein; Antibodies; Autopsy; Behavioral; Binding; Biochemical; Biological Assay; Biological Markers; Brain; Cells; Clinic; Clinical Research; Clinical Trials; Cognition; Collaborations; Complex; Core Facility; Cultured Cells; Data; Deacetylase; Diagnosis; Diagnostic; Disease; Disease Progression; Dissociation; Dose; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Exhibits; Gliosis; Goals; HDAC6 gene; Hippocampus (Brain); Histologic; Human; Immunotherapy; Impaired cognition; In Vitro; Lead; Learning; Link; MAPT gene; Measures; Mediating; Memory; Microscopy; Microtubule Stabilization; Microtubules; Modeling; Modification; Molecular; Monoclonal Antibodies; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Onset of illness; Pathologic; Pathology; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Post-Translational Protein Processing; Prognostic Marker; Proteins; SIRT1 gene; Sampling; Senile Plaques; Sensitivity and Specificity; Sirtuins; Site; Specificity; Tauopathies; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Treatment Efficacy; Western Blotting; abeta accumulation; advanced disease; antibody detection; base; beta amyloid pathology; brain tissue; clinical efficacy; clinically significant; combat; disease phenotype; extracellular; human disease; immunotherapy trials; in vivo; interdisciplinary approach; mouse model; neurotoxicity; new therapeutic target; novel; novel marker; novel therapeutics; post-doctoral training; pre-clinical; prevent; prion-like; specific biomarkers; targeted treatment; tau Proteins; tau aggregation; tau function; tau mutation; tau phosphorylation; tau-1; therapeutic biomarker; tool; training opportunity; uptake

PROJECT SUMMARY/ABSTRACT: Alzheimer’s disease (AD) is a fatal, age-progressive neurodegenerative disease affecting nearly 6 million patients in the US. Currently, there is no cure for AD, and existing clinical trials have largely failed. This calls for the need to investigate new avenues to combat this disease. Recently, we and others have focused on post-translational modifications (PTM) of tau protein that mediate progression of tauopathies including AD. We identified acetylated tau as a key feature of nearly all AD patients and elucidated several pathways through which tau acetylation mediates toxicity including insoluble tau fibril formation, promoting aberrant tau hyper- phosphorylation, and causing dissociation of tau from microtubule (MTs). Furthermore, loss of key deacetylases that suppress tau acetylation including a sirtuin (SIRT1) and in our unpublished studies, the deacetylase HDAC6, is sufficient to exacerbate AD phenotypes in mice. We hypothesize that acetylated tau (Ac-Tau) represents a novel pathological strain that can be exploited therapeutically. Here, we will employ a first-of-its-kind preclinical immunotherapy study to target acetylated tau in an AD mouse model characterized by combined tau tangles and amyloid plaques. This model will better recapitulate human AD in which both tau and amyloid beta pathologies are present. By employing diverse, interdisciplinary approaches afforded by excellent UNC core facilities and collaborations, we will validate whether Ac-Tau immunotherapy can rescue AD-like neurodegeneration and cognitive decline. In Aim 1, we will screen >30 candidate monoclonal mouse antibodies via a newly developed in vitro high-throughput microscopy pipeline in tau-transfected cells to determine which candidate acetyl-tau antibodies against two specific sites (commonly observed in AD patients; K280 and K311) are most suitable for immunotherapy based on specificity and sensitivity for Ac-Tau. Preliminary data has confirmed that several antibodies are highly specific and promising. Given that Ac-Tau has been suggested as a disease-specific marker, we will investigate the utility of the Ac-tau antibodies for the detection of CSF-tau as a new AD biomarker. In Aim 2, using our most promising candidate antibodies for Ac-Tau, we will carry out an in vivo Ac-Tau immunotherapy trial in plaque/tangle bearing PS19/5xFAD mice at both early, preventative (3-6 months) and late (6-9 months) timepoints. We will perform biochemical and histological assays to assess key hallmarks of AD pathology and neurodegeneration followed by a rigorous evaluation of cognition, learning, and survival following Ac-Tau based immunotherapy. This project outlines the first in vivo immunotherapy study targeting Ac-Tau, which could potentially provide a new AD therapeutic and prognostic biomarker for use in the clinic. Furthermore, this proposal outlines a collaborative, comprehensive, and valuable post-doctoral training opportunity.

项目摘要/摘要： 阿尔茨海默病(AD)是一种致命的、年龄进行性的神经退行性疾病，影响着近600万人 在美国的病人。目前，AD还没有治愈方法，现有的临床试验在很大程度上失败了。这调用 有必要研究抗击这种疾病的新途径。最近，我们和其他人关注的是 Tau蛋白的翻译后修饰(PTM)，介导包括AD在内的tau病的进展。我们 确认乙酰化tau是几乎所有AD患者的关键特征，并阐明了几种途径 其中tau乙酰化介导的毒性包括不溶性tau原纤维的形成，促进tau的异常高分泌。 磷酸化，并导致tau从微管(MTS)解离。此外，钥匙丢失 抑制tau乙酰化的脱乙酰酶，包括sirtuin(SIRT1)，在我们未发表的研究中， 脱乙酰酶HDAC6足以加重小鼠的AD表型。我们假设乙酰化牛磺酸 (Ac-Tau)代表了一种可用于治疗的新的病理菌株。在这里，我们将使用一个 首次在AD小鼠模型中进行靶向乙酰化tau的临床前免疫治疗研究 以结合tau缠结和淀粉样斑块为特征。该模型将更好地概括人类AD 其中同时存在tau和淀粉样β蛋白的病理。通过采用多样化、跨学科的 由出色的北卡罗来纳大学核心设施和协作提供的方法，我们将验证Ac-Tau 免疫疗法可以挽救AD样神经退行性变和认知功能下降。在目标1中，我们将筛选&>30 通过一种新开发的体外高通量显微镜流水线获得候选单抗 将tau基因导入细胞，以确定针对两个特定位点(通常 在AD患者中观察到；K280和K311)最适合于基于特异性和 对Ac-Tau的灵敏度。初步数据证实，有几种抗体具有很高的特异性和前景。 鉴于ac-tau已被建议作为疾病特异性标记物，我们将调查ac-tau的效用。 抗体检测脑脊液-tau蛋白作为新的AD生物标志物在《目标2》中，使用我们最有希望的候选人 Ac-Tau抗体，我们将在体内进行Ac-Tau免疫治疗试验 PS19/5xFAD小鼠在早期、预防性(3-6个月)和晚期(6-9个月)时间点。我们将表演 随后进行生化和组织学分析，以评估AD病理和神经变性的关键特征 通过严格评估基于Ac-Tau的免疫治疗后的认知、学习和生存情况。这 该项目概述了第一项针对Ac-Tau的体内免疫治疗研究，这可能会提供一种新的 临床上使用的AD治疗和预后生物标志物。此外，该提案还概述了 协作性、综合性和宝贵的博士后培训机会。