Stage-specific Impact of TNF-alpha Receptor Signaling in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见的痴呆症，其特征是记忆力逐渐衰退，认知功能减弱，行为改变，困扰着近50%85岁及以上的人。AD相关的病理以时间和空间的方式演变，表现为A2肽沉积、神经纤维缠结形成、突触完整性降低和神经元丢失。尽管AD的病因尚不清楚，但压倒性的数据支持炎症是影响这些基本病理的发展和严重程度的主要因素，因为细胞因子和其他炎症分子的广泛产生以及小胶质细胞的激活已参与疾病过程。我们的实验室对解剖AD早期症状前阶段活跃的炎症信号级联感兴趣，因为深入了解这些过程可能有助于开发真正改善疾病的治疗策略。本实验室利用3xTg-AD小鼠模型，以进行性和年龄依赖性的方式显示斑块和tau病理，是迄今为止最具代表性的人类AD小鼠模型。我们之前已经证明，在3xTg-AD小鼠中，强大的促炎分子肿瘤坏死因子-α(TNF-1)在发生标志性淀粉样蛋白和tau病理之前的年龄就上调(Janelsins等人，2005年)，并且这种细胞因子在3xTg-AD小鼠中的慢性表达会导致显著的神经元死亡(Janelsins等人，2008年)。尽管对肿瘤坏死因子的功能和信号在外周免疫反应中的作用已知很多，但目前尚不清楚肿瘤坏死因子受体、肿瘤坏死因子受体和肿瘤坏死因子受体对阿尔茨海默病下游致病信号级联反应的脑特异性作用。我们假设，在阿尔茨海默病的病理前阶段和既往疾病的背景下，选择性地取消肿瘤坏死因子受体的表达将不同地影响阿尔茨海默病中淀粉样蛋白和tau病变的严重程度以及相关的神经炎症。我们打算采用两种策略来检验这一假说：(1)已建立了3xTgAD小鼠，以研究全局去除肿瘤坏死因子受体表达对病理进展的影响；(2)已设计、测试并将小抑制RNA(siRNA‘s)工程入腺相关病毒(AAV)载体，以选择性和慢性地下调体内肿瘤坏死因子-RI或RII的表达，以剖析肿瘤坏死因子-1信号在AD发病机制中的疾病阶段特异性作用。 公共卫生相关性：阿尔茨海默病(AD)是最常见的与年龄相关的神经退行性疾病，大约20%的80岁以上的人和大约40%的85岁以上的人受到影响。在美国，大约50%的养老院居民受到AD的影响，导致每年的累计成本超过650亿美元。随着人口老龄化，阿尔茨海默病的发病率将急剧增加，到2050年，估计将有1100万至1600万美国人患有阿尔茨海默病，这使得对这种毁灭性疾病的诊断、治疗和预防的研究具有重大的国家意义。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent form of dementia characterized by progressive memory deterioration, diminished cognitive function, and altered behavior afflicting nearly 50% of individuals 85 years and older. AD-related pathologies evolve in a temporal and spatial manner as evidenced by A2 peptide deposition, neurofibrillary tangle formation, decreased synaptic integrity, and neuronal loss. Although the etiology of AD is unknown, overwhelming data support inflammation as being a major player influencing the development and severity of these cardinal pathologies, as extensive production of cytokines and other inflammatory molecules and the activation of microglia have been implicated in the disease process. Our laboratory is interested in dissecting the inflammatory signaling cascades active during the early pre- symptomatic stages of AD, as insight into these processes may facilitate the development of therapeutic strategies that are truly disease ameliorating. Our laboratory utilizes the 3xTg-AD mouse model of AD, which exhibits plaque and tau pathology in a progressive and age-dependent manner and to date, is the most representative mouse model of human AD. We have previously shown that the potent pro-inflammatory molecule, tumor necrosis factor-alpha (TNF-1), is up-regulated in 3xTg-AD mice at ages preceding the development of hallmark amyloid and tau pathologies (Janelsins et al., 2005), and that chronic expression of this cytokine in 3xTg-AD mice leads to marked neuronal death (Janelsins et al., 2008). Although much is known about TNF- function and signaling in peripheral immune responses, the relative brain-specific contributions of each cognate receptor of TNF- , TNF-RI and TNF-RII, to the downstream pathogenic signaling cascades in AD are presently unknown. We hypothesize that selective abrogation of TNF- receptor expression at a pre-pathologic stage and in the context of established disease will differentially impact the severity of amyloid and tau pathologies and associated neuroinflammation in Alzheimer's disease. We intend to employ two strategies to test this hypothesis: (1) 3xTgAD mice lacking TNF-RI and TNF-RII have been created to study the effects global ablation of TNF- receptor expression has on pathological progression; and (2) small inhibitory RNA's (siRNA's) have been designed, tested, and engineered into adeno-associated virus (AAV) vector to selectively and chronically knock down TNF-RI or RII expression in vivo to dissect the disease stage-specific role of TNF-1 signaling during AD pathogenesis. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common age-related neurodegenerative disorder affecting approximately 20 percent of individuals over age 80 and approximately 40 percent of those over age 85. Approximately fifty percent of nursing home residents in the United States are affected by AD contributing to an annual cumulative cost exceeding 65 billion dollars. As the population ages, the incidence of AD will increase dramatically, and by 2050 it is estimated that between 11 and 16 million Americans will be living with AD, making research in diagnosis, treatment, and prevention of this devastating disease a matter of great national importance.