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： 阿尔茨海默氏病（AD）是一种致命的，年龄的神经退行性疾病，影响了近600万 美国的患者。目前，尚无广告的治愈方法，现有的临床试验在很大程度上失败了。这会打电话 为了调查新途径以应对这种疾病。最近，我们和其他人专注于 tau蛋白的翻译后修饰（PTM），包括AD在内的金皮病的中位进展。我们 将乙酰化的tau鉴定为几乎所有AD患者的关键特征，并阐明了多个途径 tau乙酰化介导了毒性，包括无法差的tau纤维形成，促进异常tau超级 磷酸化，并导致Tau从微管（MTS）解离。此外，损失钥匙 抑制tau乙酰化的脱乙酰基酶，包括sirtuin（SIRT1），在我们未发表的研究中 脱乙酰基酶HDAC6足以加剧小鼠的AD表型。我们假设乙酰化的tau （AC-TAU）代表一种可以热探索的新型病理菌株。在这里，我们将采用 在AD小鼠模型中靶向乙酰化tau的首先临床前免疫疗法研究 以tau缠结和淀粉样斑块的结合为特征。该模型将更好地概括人类广告 其中存在TAU和淀粉样β病理学。通过雇用潜水员，跨学科 优秀的UNC核心设施和合作提供的方法，我们将验证AC-TAU是否 免疫疗法可以挽救类似AD的神经变性和认知能力下降。在AIM 1中，我们将筛选> 30 通过新开发的体外高通量显微镜管道中候选单克隆小鼠抗体 TAU转染的细胞确定哪种候选乙酰基-TAU抗体针对两个特定位点（通常 在AD患者中观察到； K280和K311）最适合基于特异性和 对AC-TAU的敏感性。初步数据已经证实了几种抗体是高度特异性和有希望的。 鉴于已建议AC-TAU作为特异性标记，我们将研究AC-TAU的效用 CSF-TAU作为新的AD生物标志物检测的抗体。在AIM 2中，使用我们最有前途的候选人 AC-TAU的抗体，我们将在牙菌斑/缠结轴承中进行体内AC-TAU免疫疗法试验 PS19/5XFAD小鼠在早期，预防性（3-6个月）和晚期（6-9个月）时点。我们将表演 遵循AD病理学和神经退行性的关键标志的生化和组织学评估。 通过对基于AC-TAU的免疫疗法后对认知，学习和生存的严格评估。这 项目概述了第一个针对AC-TAU的体内免疫疗法研究，该研究可能会提供新的 AD热和预后生物标志物用于诊所。此外，该提议概述了 协作，全面和宝贵的博士后培训机会。