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: 10588253
• 负责人: Miles Richard Bryan
• 金额: $ 7.43万
• 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/10588253
• 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; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Exhibits; Genes; Gliosis; Goals; HDAC6 gene; Hippocampus; Histologic; Human; Immunotherapy; Impaired cognition; In Vitro; 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; Predisposition; Prognostic Marker; Proteins; Sampling; Senile Plaques; Sensitivity and Specificity; Sirtuins; Site; Specificity; Tauopathies; Testing; Therapeutic; Toxic effect; Transfection; Transgenic Organisms; Treatment Efficacy; Western Blotting; abeta accumulation; advanced disease; antibody detection; beta amyloid pathology; brain tissue; clinical efficacy; clinically significant; combat; disease phenotype; extracellular; human disease; hyperphosphorylated tau; 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-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.

项目总结/摘要： 阿尔茨海默病（AD）是一种致命的、年龄进行性神经退行性疾病，影响近600万人 美国的病人。目前，AD还没有治愈方法，现有的临床试验基本上都失败了。这要求 需要研究新的方法来对抗这种疾病。最近，我们和其他人关注了 tau蛋白的翻译后修饰（PTM），其介导包括AD在内的tau蛋白病的进展。我们 确定乙酰化tau蛋白是几乎所有AD患者的关键特征，并通过以下途径阐明了几种途径： 所述tau乙酰化介导毒性，包括不溶性tau原纤维形成，促进异常tau超表达， 在一些实施方案中，tau蛋白可以被磷酸化，并且引起tau蛋白从微管（MT）解离。此外，钥匙丢失 抑制tau乙酰化的脱乙酰酶，包括沉默调节蛋白（SIRT 1），在我们未发表的研究中， 脱乙酰酶HDAC 6足以加重小鼠中的AD表型。我们假设乙酰化tau蛋白 （Ac-Tau）代表了可以在治疗上利用的新的病理菌株。在这里，我们将使用一个 首个在AD小鼠模型中靶向乙酰化tau蛋白的临床前免疫治疗研究 其特征在于组合的tau缠结和淀粉样斑块。该模型将更好地概括人类AD 其中存在tau和淀粉样蛋白β病理。通过采用多样化、跨学科的 通过优秀的核心设施和合作提供的方法，我们将验证Ac-Tau是否 免疫疗法可以挽救AD样神经变性和认知衰退。在目标1中，我们将筛选>30 候选单克隆小鼠抗体通过一个新开发的体外高通量显微镜管道， tau转染的细胞，以确定针对两个特定位点（通常为 在AD患者中观察到; K280和K311）最适合于基于特异性的免疫疗法， Ac-Tau的灵敏度。初步数据已经证实，几种抗体具有高度特异性和前景。 鉴于Ac-Tau已被建议作为疾病特异性标志物，我们将研究Ac-Tau的效用。 用于检测CSF-tau作为新的AD生物标志物的抗体。在目标2中，使用我们最有希望的候选人 为了获得Ac-Tau的抗体，我们将在带有斑块/缠结的患者中进行体内Ac-Tau免疫治疗试验， 在早期、预防性（3-6个月）和晚期（6-9个月）时间点的PS19/5xFAD小鼠。我们将执行 生物化学和组织学测定以评估AD病理学和神经变性的关键标志， 通过对基于Ac-Tau的免疫疗法后的认知、学习和存活的严格评估。这 该项目概述了第一个针对Ac-Tau的体内免疫治疗研究，这可能会提供一种新的 用于临床的AD治疗和预后生物标志物。此外，该提案概述了一个 合作，全面，宝贵的博士后培训机会。