Improved Transgenic Mouse Model of Alzheimer's Disease

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。随着预期寿命的增加，AD病例数量预计将从今天的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的对症治疗，并且没有批准的疾病改善治疗。开发AD疗法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”存在两个主要缺陷：1）未能概括完整的疾病表型，和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一个更完整的AD转基因小鼠模型，其中AD-淀粉样蛋白（A）中的AD相关突变驱动野生型人类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的标志性神经病理学病变、淀粉样蛋白斑块和神经纤维缠结之外，在大量AD个体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AD是一种“多蛋白病”，其中A？、tau、α-突触核蛋白和可能的TDP-43相加或协同作用损害认知并引起神经变性。作为测试该假设的初始步骤，我们提出创建以各种比例表达具有AD连锁突变的人APP、野生型人tau和野生型α-突触核蛋白的转基因小鼠。我们将1）确定α-突触核蛋白对A <$40、A <$42和人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病理学的影响; 3）确定α-突触核蛋白对神经变性的影响;和4）确定α-突触核蛋白对认知功能的影响，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、α-突触核蛋白）的转基因小鼠的表型。无论病因如何，混合性病变患者发生临床痴呆的可能性明显高于单纯斑块和缠结患者。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病疗法的效果在分配给普通人群时可能会有所不同。开发AD的小鼠模型，包括混合病理，将代表一个重大的进步，可能会增加在小鼠中的临床前研究的预测有效性。

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.