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

3xTg-AD 小鼠中基于基因的 TNF-α 活性调节

• 批准号: 7385895
• 负责人: WILLIAM J. BOWERS
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385895
• 关键词: Affect; Age; Age-Months; Alkaline Phosphatase; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Appearance; Astrocytes; Biological Models; Brain; Cells; Chronic; Data; Dementia; Deterioration; Disease; Disease Outcome; Disease Progression; Elevation; Emotional; Enzyme-Linked Immunosorbent Assay; Event; Foundations; Functional disorder; Gene Expression; Genes; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Hippocampus (Brain); Human; Immune; Immunoblotting; Individual; Inflammation; Inflammatory; Inflammatory Response; Intestines; Laboratories; Measures; Mediating; Mediator of activation protein; Messenger RNA; Microglia; Modeling; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Outcome; Pathogenesis; Pathology; Pattern; Persons; Phosphorylation; Play; Population; Prevalence; Principal Investigator; Process; Production; Recombinant adeno-associated virus (rAAV); Research; Role; Senile Plaques; Severities; Signal Transduction; Signaling Molecule; Staging; Synapses; TNF gene; Time; Transcript; Transcriptional Activation; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Up-Regulation; Western Blotting; Work; adeno-associated viral vector; age related; amyloid pathology; base; cytokine; demographics; disorder control; entorhinal cortex; functional decline; human TNF protein; immunogenic; insight; interest; mild neurocognitive impairment; mouse model; neuron loss; novel; novel therapeutics; programs; protein expression; research study; response; socioeconomics; tau Proteins; tau function; therapeutic target

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.

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，与进行性功能下降、痴呆和神经元损失相关，影响约40%的85岁以上的人。人口统计数据表明，随着世界人口中位年龄的增加，AD的患病率和社会经济负担将大幅增加。该疾病的病理学标志包括淀粉样蛋白β（A3）斑块和神经纤维缠结，其在阿尔茨海默病的致病机制中起关键作用，以时间和空间方式演变。我们有兴趣了解导致或维持AD发病机制时空进展的早期机制。已经提出炎症过程对于在脑内引发和/或传播AD相关病理是不可或缺的，因为炎症细胞因子表达和其他炎症标志物的阐述在具有已知AD病理的个体中更明显。最近，已经创建了发展淀粉样蛋白和tau病理的AD的3xTg-AD小鼠模型，其是迄今为止描述人类阿尔茨海默病中发生的情况的最疾病相关的模型系统。我们已经观察到在明显的淀粉样病变发生之前，在该模型中促炎细胞因子TNF-α的显著上调。由于TNF-a已被证明在患有轻度认知障碍和阿尔茨海默病的人中增强，3xTg-AD小鼠提供了一种新的范例，其中研究了这种细胞因子在早期疾病阶段的作用。我们假设TNF-α介导的炎症使AD模型中的疾病持续存在，其中存在对淀粉样蛋白和tau病理的遗传易感性，并且抑制这种炎症反应将减少病理性淀粉样蛋白和tau结果。此外，我们假设在炎症发作之前的炎症事件的局灶性诱导将以区域和时间的方式加剧病理结果。我们将施用重组腺相关病毒（rAAV）载体，其表达TNF-α以产生持续的局灶性炎症反应或表达TNF受体拮抗剂以在现有病理之前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见解，并可能阐明新的治疗靶点。