Improved Transgenic Mouse Model of Alzheimer's Disease

改良的阿尔茨海默病转基因小鼠模型

• 批准号: 8244853
• 负责人: Karen H Ashe
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244853
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Animal Model; Brain; Brain region; Characteristics; Clinical; Cognitive deficits; Comorbidity; DNA-Binding Proteins; Dementia; Deposition; Detection; Development; Disease; Etiology; Failure; Frontotemporal Lobar Degenerations; General Population; Genetic Variation; Human; Impaired cognition; Individual; Intervention; Lesion; Lewy Bodies; Life Expectancy; Link; Memory Loss; Methods; Modeling; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Parkinson Disease; Pathogenesis; Pathologic Processes; Pathology; Persons; Pharmaceutical Preparations; Phase; Phenotype; Prevention therapy; Proteins; Public Health; Reporting; Rodent Model; Senile Plaques; Simulate; Substantia nigra structure; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; alpha synuclein; clinical Diagnosis; cognitive function; disease phenotype; human disease; improved; meetings; mouse model; neuron loss; neuropathology; pre-clinical; preclinical study; presenilin; prevent; research clinical testing; synuclein; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is on the verge of becoming a worldwide public health crisis. As life expectancy increases, the number of AD cases is expected to increase from 35 million today to more than 115 million by 2050. Currently only two classes of drugs are approved for symptomatic treatment of AD, and there are no approved disease-modifying treatments. A serious impediment to the development of AD therapies is the lack of adequate rodent models for pre-clinical testing. There are two major deficiencies of current transgenic mouse "models of AD": 1) the failure to recapitulate the complete disease phenotype, and 2) the failure to incorporate mixed pathologies or co-morbidities that occur in approximately half of individuals with a clinical diagnosis of AD. The proposed project is an attempt to create a more complete transgenic mouse model of AD, in which AD-linked mutations in ¿-amyloid (A¿) drive pathological changes in wild-type human tau, leading to neurodegeneration and severe cognitive deficits. Such a model is essential for pre-clinical testing of potential therapies for the prevention of symptomatic AD. In addition to the hallmark neuropathological lesions of AD, amyloid plaques and neurofibrillary tangles, abnormal inclusions composed of aggregated a-synuclein and ubiquitinated TAR DNA-binding protein 43 (TDP-43) have been observed in a substantial number of individuals with AD. We hypothesize that AD is a "polyproteinopathy" in which A¿, tau, a-synuclein, and possibly TDP-43 act additively or synergistically to impair cognition and cause neurodegeneration. As the initial step in testing this hypothesis, we propose to create transgenic mice that express human APP with an AD- linked mutation, wild-type human tau, and wild-type a-synuclein, in various proportions. We will 1) determine the effect of a-synuclein on levels of A¿40, A¿42 and human tau; 2) determine the effect of a-synuclein on amyloid load and neurofibrillary pathology; 3) determine the effect of a-synuclein on neurodegeneration; and 4) determine the effect of a-synuclein on cognitive function, by comparing the phenotypes of bigenic mice expressing APP and tau transgenes to the phenotypes of transgenic mice expressing all three transgenic proteins (APP, tau, a-synuclein). Regardless of etiology, the likelihood of clinical dementia is significantly greater in persons who have mixed pathology than in individuals with plaques and tangles alone. There is therefore concern that the effects of new Alzheimer therapies that are initially tested in mouse models and humans with pure AD may differ when they are dispensed to the general population. The development of mouse models of AD that incorporate mixed pathologies would represent a significant advancement that is likely to increase the predictive validity of pre-clinical studies in mice.

描述（由申请人提供）： 阿尔茨海默病（AD）正处于成为全球性公共卫生危机的边缘。随着预期寿命的延长，AD 病例数量预计将从现在的 3500 万增加到 2050 年的 1.15 亿以上。目前只有两类药物被批准用于 AD 对症治疗，并且没有批准的疾病缓解治疗方法。 AD疗法发展的一个严重障碍是缺乏足够的啮齿动物模型进行临床前测试。目前的转基因小鼠“AD模型”有两个主要缺陷：1）未能重现完整的疾病表型，2）未能纳入大约一半临床诊断为AD的个体中出现的混合病理或共病。该项目试图创建一个更完整的 AD 转基因小鼠模型，其中与 AD 相关的 ¿-淀粉样蛋白 (A¿) 突变会驱动野生型人类 tau 蛋白发生病理变化，导致神经退行性变和严重的认知缺陷。这样的模型对于预防症状性 AD 的潜在疗法的临床前测试至关重要。除了 AD 的标志性神经病理学病变、淀粉样蛋白斑和神经原纤维缠结之外，在大量 AD 患者中还观察到由聚集的 α-突触核蛋白和泛素化 TAR DNA 结合蛋白 43 (TDP-43) 组成的异常包涵体。我们假设 AD 是一种“多蛋白病”，其中 A¿、tau、α-突触核蛋白和可能的 TDP-43 叠加或协同作用，损害认知并导致神经变性。作为检验这一假设的第一步，我们建议创建转基因小鼠，以不同的比例表达具有 AD 相关突变的人类 APP、野生型人类 tau 和野生型 a-突触核蛋白。我们将 1) 确定 a-突触核蛋白对 A¿40、A¿42 和人类 tau 水平的影响； 2)确定α-突触核蛋白对淀粉样蛋白负荷和神经原纤维病理学的影响； 3)确定α-突触核蛋白对神经变性的影响； 4) 通过比较表达 APP 和 tau 转基因的双基因小鼠的表型与表达所有三种转基因蛋白（APP、tau、a-突触核蛋白）的转基因小鼠的表型，确定 a-突触核蛋白对认知功能的影响。无论病因如何，具有混合病理学的人患临床痴呆的可能性明显高于仅患有斑块和缠结的人。因此，人们担心，最初在小鼠模型和患有纯 AD 的人类中测试的新阿尔茨海默疗法的效果在向普通人群分发时可能会有所不同。包含混合病理学的 AD 小鼠模型的开发将代表着一项重大进步，可能会提高小鼠临床前研究的预测有效性。