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)正处于成为世界性公共卫生危机的边缘。随着预期寿命的延长，预计到2050年，AD病例数量将从今天的3500万增加到1.15亿以上。目前只有两类药物被批准用于AD的对症治疗，并且没有被批准的疾病修改治疗。AD治疗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)未能概括完整的疾病表型；2)未能纳入在大约一半的临床诊断为AD的个体中发生的混合病理或共病。拟议的项目是试图创建更完整的阿尔茨海默病转基因小鼠模型，在该模型中，AD相关的淀粉样蛋白(A？)突变会导致野生型人类tau的病理变化，导致神经退化和严重的认知缺陷。这样的模型对于预防症状性AD的潜在疗法的临床前测试是必不可少的。除了AD的标志性神经病理损害、淀粉样斑块和神经纤维缠结外，在相当数量的AD患者中还观察到由聚集的α-突触核蛋白和泛素化的TAR DNA结合蛋白43(TDP-43)组成的异常包涵体。我们假设阿尔茨海默病是一种“多蛋白病”，其中Aβ、tau、α-突触核蛋白，可能还有TDP-43共同或协同作用，损害认知，导致神经变性。作为检验这一假说的第一步，我们建议创建转基因小鼠，以不同的比例表达带有AD相关突变的人APP、野生型人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纤维病理的影响；3)确定a-突触核蛋白对神经退行性变的影响；以及4)通过比较表达APP和tau转基因双基因小鼠的表型和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，患有混合病理的人患临床痴呆症的可能性明显高于仅有斑块和缠结的人。因此，人们担心，最初在患有纯阿尔茨海默病的小鼠模型和人类身上测试的新阿尔茨海默病疗法在分发给普通人群时，效果可能会不同。合并混合病理的AD小鼠模型的发展将代表着一项重大进步，可能会增加小鼠临床前研究的预测有效性。