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: 8264188
• 负责人: Sara Lynn Montgomery
• 金额: $ 3.77万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264188
• 关键词: Ablation; Affect; Age; Aged, 80 and over; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Automobile Driving; 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; Play; Population; Prevention; Process; Production; RNA; Receptor Signaling; Receptors, Tumor Necrosis Factor, Type II; Relative (related person); Research; Role; Severities; Signal Transduction; Small Interfering RNA; Staging; Synapses; TNF gene; Technology; Testing; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States; abstracting; adeno-associated viral vector; age related; cognitive function; cost; cytokine; design; human TNFRSF1A protein; human very old age (85+); improved; in vivo; insight; interest; knock-down; mouse model; neurofibrillary tangle formation; neuroinflammation; neuron loss; pre-clinical; receptor; receptor expression; tau Proteins; therapeutic development; tumor necrosis factor alpha receptor

6. Project Summary/Abstract 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 ABeta 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 presymptomatic 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-alpha), 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-alpha function and signaling in peripheral immune responses, the relative brain-specific contributions of each cognate receptor of TNF-alpha, TNF-RI and TNF-RII, to the downstream pathogenic signaling cascades in AD are presently unknown. We hypothesize that selective abrogation of TNF-alpha 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-alpha 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-alpha signaling during AD pathogenesis.

6.项目总结/摘要 阿尔兹海默症阿尔茨海默病（AD）是最普遍的痴呆形式，其特征在于进行性记忆退化、认知功能减退和行为改变，困扰近50%的85岁及以上的个体。AD相关的病理以时间和空间的方式发展，如通过ABeta肽沉积、神经元缠结形成、突触完整性降低和神经元损失所证明的。尽管AD的病因学尚不清楚，但大量数据支持炎症是影响这些主要病理学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活化与疾病过程有关。我们的实验室有兴趣解剖在AD的早期症状前阶段活跃的炎症信号级联反应，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。我们的实验室利用AD的3xTg-AD小鼠模型，其以进行性和年龄依赖性的方式表现出斑块和tau病理学，并且迄今为止，是人类AD的最具代表性的小鼠模型。我们先前已经表明，在发展标志性淀粉样蛋白和tau病理之前的年龄，有效的促炎分子肿瘤坏死因子-α（TNF-α）在3xTg-AD小鼠中上调（Janelsins等人，2005），并且该细胞因子在3xTg-AD小鼠中的慢性表达导致显著的神经元死亡（Janelsins等人，2008年）。虽然对TNF-α在外周免疫应答中的功能和信号传导有很多了解，但TNF-α的每个同源受体TNF-RI和TNF-RII对AD中下游致病性信号传导级联的相对脑特异性贡献目前尚不清楚。我们假设，在病理前阶段和已确诊疾病的背景下，选择性废除TNF-α受体表达将对阿尔茨海默病中淀粉样蛋白和tau蛋白病理学的严重程度以及相关的神经炎症产生差异性影响。我们打算采用两种策略来验证这一假设：（1）建立缺乏TNF-RI和TNF-RII的3xTgAD小鼠，以研究TNF-α受体表达的整体消除对病理进展的影响;（2）小抑制性RNA（siRNA）已经设计、测试，并被工程化到腺相关病毒（AAV）载体中，以选择性地和长期地敲低体内TNF-RI或RII表达，从而剖析TNF-RI或RII的疾病阶段特异性作用。AD发病机制中的α信号传导。