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

TNF-α 受体信号传导对阿尔茨海默病的阶段特异性影响

• 批准号: 7995001
• 负责人: Sara Lynn Montgomery
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995001
• 关键词: Ablation; Affect; Age; Aged, 80 and over; Alzheimer' s Disease; American; Amyloid; Behavior; Brain; Cessation of life; Chronic; Data; Dementia; Deposition; Deterioration; Development; Diagnosis; Disease; Engineering; Etiology; Exhibits; Human; Immune response; Incidence; Individual; Inflammation; Inflammatory; Laboratories; Life; Memory; Microglia; Mus; Neurodegenerative Disorders; Neurons; Nursing Homes; Pathogenesis; Pathologic; Pathology; Peptides; Peripheral; Population; Prevention; Process; Production; Receptor Signaling; Receptors, Tumor Necrosis Factor, Type II; Relative (related person); Research; Role; Severities; Signal Transduction; Staging; Synapses; TNF gene; Testing; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States; adeno-associated viral vector; age related; cognitive function; cost; cytokine; design; human TNF protein; human very old age (85+); in vivo; insight; interest; knock-down; mouse model; neurofibrillary tangle formation; neuroinflammation; neuron loss; public health relevance; receptor expression; tau Proteins; therapeutic development

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.

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症形式，其特征是进行性记忆退化，认知功能下降和行为改变，困扰着近50%的85岁及以上的个体。A2肽沉积、神经原纤维缠结形成、突触完整性降低和神经元丢失等都证明了ad相关病理的时间和空间演变。尽管阿尔茨海默病的病因尚不清楚，但大量数据支持炎症是影响这些主要病理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大量产生以及小胶质细胞的激活与疾病过程有关。我们的实验室对在阿尔茨海默病早期症状前阶段活跃的炎症信号级联很感兴趣，因为对这些过程的深入了解可能有助于开发真正改善疾病的治疗策略。我们实验室采用3xTg-AD小鼠AD模型，该模型表现出斑块和tau蛋白病理进展和年龄依赖性，是迄今为止最具代表性的人类AD小鼠模型。我们之前的研究表明，在发生淀粉样蛋白和tau蛋白病变之前，3xTg-AD小鼠体内的强效促炎分子肿瘤坏死因子- α (TNF-1)上调（Janelsins et al., 2005），并且3xTg-AD小鼠体内这种细胞因子的慢性表达会导致显著的神经元死亡（Janelsins et al., 2008）。尽管人们对TNF-的功能和外周免疫反应中的信号传导已经了解很多，但TNF-、TNF- ri和TNF- rii的每一种同源受体在AD下游致病性信号级联反应中的相对脑特异性贡献目前尚不清楚。我们假设，在病理前阶段和既定疾病的背景下，选择性地取消TNF-受体表达将对阿尔茨海默病中淀粉样蛋白和tau病理学以及相关神经炎症的严重程度产生不同的影响。我们打算采用两种策略来验证这一假设：(1)创建缺乏TNF- ri和TNF- rii的3xTgAD小鼠，研究TNF-受体表达的整体消融对病理进展的影响；(2)小抑制RNA （siRNA）已被设计、测试并工程化成腺相关病毒（AAV）载体，在体内选择性和慢性地敲低TNF-RI或RII的表达，以解剖TNF-1信号在AD发病过程中的疾病阶段特异性作用。