Investigating Mechanisms of Neurodegeneration in Transgenic Mouse Models of Tauopathies

研究 Tau蛋白病转基因小鼠模型中神经变性的机制

• 批准号: 10372933
• 负责人: Yuxing Xia
• 金额: $ 4.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2025-03-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372933
• 关键词: 3xTg-AD mouse; AD transgenic mice; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Antibodies; Biochemistry; Biological Markers; Brain; Brain region; Cell Count; Clinical; Cognitive deficits; Cryoelectron Microscopy; Cultured Cells; Disease; Disease Progression; Fellowship; Frontotemporal Dementia; Genes; Goals; Golgi Apparatus; Hippocampus (Brain); Histopathology; Human; Immunotherapy; Impaired cognition; Longevity; Memory Loss; Memory impairment; Modeling; Molecular; Monoclonal Antibodies; Mosaicism; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathology; Persons; Pharmacotherapy; Phenotype; Phosphorylation; Pick body; Rapid screening; Reproducibility; Research Proposals; Role; Severities; Stains; Structure; Symptoms; Tauopathies; Testing; Therapeutic; Therapeutic Studies; Time; Training; Transgenic Mice; Translational Research; base; behavior test; cerebral atrophy; clinical predictors; disease mechanisms study; disease phenotype; disease-causing mutation; effectiveness testing; familial Alzheimer disease; hyperphosphorylated tau; interdisciplinary approach; mouse model; neurotoxicity; novel; novel therapeutics; screening; tau Proteins; tau aggregation; tau expression; tau mutation; tau phosphorylation; tau-1; transmission process; uptake

Project Summary/Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease that affects over 25 million people worldwide. In AD, hyperphosphorylated tau inclusions like neurofibrillary tangles are one of the earliest changes and can predict clinical severity. As tau inclusions increase, cognitive decline and memory loss worsen over time. Since familial and sporadic AD share the same pathology and clinical symptoms, transgenic mice that express human tau can effectively model AD. However, many existing tau mouse models do not develop both cognitive deficits and robust pathology in the cortex and hippocampus, which are the primary regions of neurodegeneration in AD. In the field, there is a compelling need to develop an effective animal model of tauopathies for mechanistic and therapeutic studies. A good model of tauopathies must meet at least four criteria: 1) develops progressive phosphorylated tau inclusions; 2) affects the primary brain regions of cortex and hippocampus like in AD patients; 3) causes cognitive deficits; and 4) is reproducible with stable germline transmission. To meet this demand, my main translational research goal is to develop a robust animal model for 1. studying disease mechanisms of tau aggregation and hyperphosphorylation and for 2. rapid screening of drugs and therapies. Given that mice have much shorter lifespans, expression of a single disease-causing mutation may not be sufficient to induce a robust disease phenotype. In the field of neurodegeneration, multiple pathogenic mutations are commonly used to accelerate disease phenotypes in transgenic mice. For example, 3XTg-AD and 5XFAD mouse models use three and five different mutations of multiple genes respectively. As a result, I chose to enhance tau neurotoxicity by combining two disease-causing mutations (P301S/S320F) in the same gene. For this research proposal, my lab and I used pronuclear integration to generate novel transgenic mice for stable germline expression of the tau mutations P301S/S320F. With this unprecedent mouse model, I will determine the role of tau hyperphosphorylation in promoting tau aggregation, cognitive deficits and brain atrophy in Specific Aims 1 and 2. In Specific Aim 3, I will use this novel mouse model to screen phospho-tau immunotherapies. Upon completion of this study, I will fulfill my fellowship training goals of studying disease mechanisms of tau- induced neurodegeneration and developing novel immunotherapies for the treatment of AD.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的神经退行性疾病，影响超过 2500 万人 全世界。在 AD 中，过度磷酸化的 tau 蛋白包涵体（如神经原纤维缠结）是最早的变化之一 并可以预测临床严重程度。随着 tau 蛋白内含物的增加，认知能力下降和记忆力丧失会随着时间的推移而恶化。 由于家族性和散发性 AD 具有相同的病理学和临床症状，表达 人类tau蛋白可以有效地模拟AD。然而，许多现有的 tau 小鼠模型并没有发展出认知能力。 皮质和海马体的缺陷和强大的病理学，这是神经退行性变的主要区域 在公元。在该领域，迫切需要开发一种有效的 tau蛋白病动物模型来进行机制研究。 和治疗研究。一个好的 tau蛋白病模型必须至少满足四个标准：1）发展为渐进性 磷酸化 tau 内含物； 2）影响大脑皮层和海马体的主要区域，就像AD患者一样； 3）导致认知缺陷； 4) 可重复且具有稳定的种系传播。 为了满足这一需求，我的主要转化研究目标是开发一个强大的动物模型，用于 1. 研究 2. tau蛋白聚集和过度磷酸化的疾病机制以及药物和药物的快速筛选 疗法。鉴于小鼠的寿命要短得多，单一致病突变的表达可能 不足以诱导强大的疾病表型。在神经退行性疾病领域，多种致病性 突变通常用于加速转基因小鼠的疾病表型。例如，3XTg-AD 和 5XFAD小鼠模型分别使用多基因的三种和五种不同突变。结果我选择了 通过在同一基因中结合两种致病突变（P301S/S320F）来增强 tau 神经毒性。 对于这项研究计划，我和我的实验室使用原核整合来生成新型转基因小鼠，以实现稳定 tau 突变 P301S/S320F 的种系表达。有了这个史无前例的鼠标模型，我将确定 tau蛋白过度磷酸化在促进tau蛋白聚集、认知缺陷和特定脑萎缩中的作用 目标 1 和 2。在具体目标 3 中，我将使用这种新型小鼠模型来筛选磷酸化 tau 免疫疗法。 完成这项研究后，我将实现研究 tau 疾病机制的奖学金培训目标 诱导神经退行性变并开发治疗 AD 的新型免疫疗法。