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: 8413428
• 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/8413428
• 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）： 阿尔茨海默氏病（AD）即将成为全球公共卫生危机。随着预期寿命的增加，预计到2050年的AD病例数量将从今天的3500万增加到超过1.15亿。严重障碍AD疗法的是缺乏足够的啮齿动物模型进行临床前测试。当前的转基因小鼠“ AD模型”有两个主要缺陷：1）未能概括完整的疾病表型，2）未能纳入大约一半患有AD临床诊断的个体中的混合病理或合并症。拟议的项目是试图创建一个更完整的AD转基因小鼠模型，其中AD连接的 - - 淀粉样蛋白（a¿）驱动野生型人tau的病理变化，导致神经变性和严重的认知缺陷。这种模型对于预防症状AD的潜在疗法进行临床前测试至关重要。除了AD的标志性神经病理病变外，淀粉样蛋白斑块和神经原纤维缠结，由聚集的A-核蛋白和泛素化的TAR DNA结合蛋白43（TDP-43）组成的异常夹杂物，我们假设AND是一个属于“ polycoretion and and”，我们假设是一个属于“ polycoreinop and a”。 TDP-43的作用另外或协同作用是为了损害认知并引起神经退行性。作为检验这一假设的第一步，我们建议创建具有各种比例的野生型人tau和野生型A-核蛋白的转基因小鼠，以各种比例。我们将1）确定a-核蛋白对a¿40，a¿42和人类tau水平的影响； 2）确定A-突触核蛋白对淀粉样蛋白负荷和神经原纤维病理的影响； 3）确定a核蛋白对神经变性的影响； 4）通过比较表达应用程序和tau转基因的胆汁虫小鼠的表型与表达所有三种转基因蛋白（App，tau，tau，a- synnuclein）的转基因小鼠的表型来确定A-核蛋白对认知功能的影响。不管病因如何，患有斑块和缠结的人的临床痴呆症的可能性明显高。因此，人们担心在小鼠模型中最初测试的新阿尔茨海默氏症疗法的作用和纯AD的人类在分配给普通人群时可能会有所不同。结合混合病理的AD小鼠模型的发展将代表一个显着的进步，可能会增加小鼠临床前研究的预测有效性。