Gene-based TNF-alpha activity modulation in 3xTg-AD mice

描述(申请人提供)：阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，与进行性功能衰退、痴呆症和神经元丧失有关，影响85岁以上约40%的人。人口统计数据表明，随着世界人口年龄中位数的增加，阿尔茨海默病的患病率和社会经济负担将大幅增加。阿尔茨海默病的病理特征包括淀粉样β蛋白(A3)斑块和神经原纤维缠结，它们在阿尔茨海默病的发病机制中发挥关键作用，并在时间和空间上演变。我们感兴趣的是了解导致或维持AD发病的这种时间和空间进展的早期机制。炎症过程被认为是启动和/或在脑内传播AD相关病理所必需的，因为炎症细胞因子的表达和其他炎症标志物的阐述在已知AD病理的个体中更加明显。最近，一个同时发生淀粉样蛋白和tau病理的3xTg-AD小鼠模型被创建，这是迄今为止描述人类阿尔茨海默病中发生的情况的最具疾病相关性的模型系统。在此模型中，我们观察到在明显的淀粉样变发生之前，促炎细胞因子肿瘤坏死因子-a显著上调。由于有轻度认知障碍和阿尔茨海默病的人的肿瘤坏死因子-α已被证明是增强的，3xTg-AD小鼠提供了一个新的范例来研究这种细胞因子在疾病早期阶段的作用。我们假设，在AD模型中，肿瘤坏死因子-α介导的炎症使疾病持续存在，其中存在淀粉样蛋白和tau病理的遗传易感性，抑制这种炎症反应将减少病理淀粉样蛋白和tau的结果。此外，我们假设在炎症发生之前局部诱发炎症事件会以区域性和暂时性的方式加重病理结果。我们将使用表达肿瘤坏死因子-a的重组腺相关病毒(RAAV)载体来产生持续的局灶性炎症反应，或者在现有病理之前应用肿瘤坏死因子受体拮抗剂来抑制内源性炎症反应。这项工作将为炎症参与早期AD致病事件的时间和空间进展提供重要的洞察力，并可能阐明新的治疗靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive functional decline, dementia and neuronal loss affecting approximately 40 percent of persons over the age of 85 years. The demographics make evident that as the median age of the world's population increases, the prevalence and socioeconomic burden of AD will increase substantially. Pathological hallmarks of the disease include amyloid beta (A3) plaques and neurofibrillary tangles, which play a key role in the pathogenic mechanism of Alzheimer's disease, evolving in a temporal and spatial manner. We are interested in understanding the early mechanisms that cause or perpetuate this temporal and spatial progression of AD pathogenesis. Inflammatory processes have been proposed as being integral for initiating and/or propagating AD-associated pathology within the brain, as the elaboration of inflammatory cytokine expression and other markers of inflammation is more pronounced in individuals with known AD pathology. Recently, a 3xTg-AD mouse model of AD that develops both amyloid and tau pathology has been created, which to date is the most disease-relevant model system depicting what occurs in human Alzheimer's disease. We have observed significant up-regulation of the pro-inflammatory cytokine TNF-a in this model prior to the onset of overt amyloid pathology. As TNF-a has been shown to be enhanced in persons with mild cognitive impairment and Alzheimer's disease, the 3xTg-AD mouse provides a novel paradigm in which to investigate the role of this cytokine during early disease stages. We hypothesize that TNF-a mediated inflammation perpetuates disease in an AD model where genetic predisposition to amyloid and tau pathologies exist and that dampening this inflammatory response will diminish the pathological amyloid and tau outcome. Additionally, we hypothesize that the focal induction of an inflammatory event prior to the onset of inflammation will exacerbate pathological outcomes in a regional and temporal manner. We will administer recombinant adeno-associated virus (rAAV) vectors expressing either TNF-a to create a sustained focal inflammatory response or a TNF receptor antagonist to inhibit the endogenous inflammatory response prior to existing pathology. This work will provide major insight into the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially elucidate new therapeutic targets.