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: 8117126
• 负责人: Sara Lynn Montgomery
• 金额: $ 4.18万
• 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/8117126
• 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; adeno-associated viral vector; age related; cognitive function; cost; cytokine; design; human TNF protein; 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

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.

阿尔茨海默氏病 (AD) 是最常见的痴呆症，其特征是进行性记忆衰退、认知功能下降和行为改变，影响着近 50% 的 85 岁及以上人群。 AD 相关病理以时间和空间方式演变，如 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所证明。尽管 AD 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激活与疾病过程有关。我们的实验室有兴趣剖析 AD 早期症状前阶段活跃的炎症信号级联，因为深入了解这些过程可能有助于制定真正改善疾病的治疗策略。我们实验室使用的 3xTg-AD 小鼠 AD 模型，该模型以渐进和年龄依赖性的方式表现出斑块和 tau 病理学，是迄今为止最具代表性的人类 AD 小鼠模型。我们之前已经表明，强效促炎分子肿瘤坏死因子-α (TNF-1) 在 3xTg-AD 小鼠中，在出现标志性淀粉样蛋白和 tau 病理之前的年龄上调（Janelsins 等人，2005），并且这种细胞因子在 3xTg-AD 小鼠中的慢性表达会导致显着的神经元死亡（Janelsins 等人，2005）。 2008）。尽管人们对 TNF-α 在外周免疫反应中的功能和信号传导了解很多，但 TNF-α、TNF-RI 和 TNF-RII 的每种同源受体对 AD 下游致病信号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定疾病的背景下选择性废除 TNF 受体表达将对阿尔茨海默病中淀粉样蛋白和 tau 蛋白病理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检验这一假设：（1）创建缺乏 TNF-RI 和 TNF-RII 的 3xTgAD 小鼠来研究 TNF-受体表达的整体消融对病理进展的影响； (2) 小抑制性 RNA (siRNA) 已被设计、测试并工程化到腺相关病毒 (AAV) 载体中，以选择性地长期敲低体内 TNF-RI 或 RII 的表达，以剖析 TNF-1 信号在 AD 发病过程中的疾病阶段特异性作用。