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

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衰退、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A2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，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-1）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）。虽然对外周免疫应答中的TNF-α功能和信号传导有很多了解，但TNF-α、TNF-RI和TNF-RII的每种同源受体对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，在病理前阶段和在确定的疾病背景下选择性废除TNF受体表达将差异性地影响阿尔茨海默病中淀粉样蛋白和tau蛋白病理学的严重程度和相关的神经炎症。我们打算采用两种策略来验证这一假设：（1）已经建立了缺乏TNF-R I和TNF-R II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;和（2）小抑制RNA（siRNA）已经被设计，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。1信号通路。

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.