Novel Mouse Modeling to Dissect AD Pathophysiology

剖析 AD 病理生理学的新型小鼠模型

• 批准号: 7027742
• 负责人: WILLIAM J. BOWERS
• 金额: $ 26.23万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027742
• 关键词: Alzheimer' s disease; active immunization; amyloid proteins; biomarker; cerebral degeneration; disease /disorder model; entorhinal cortex; gene expression profiling; genetically modified animals; hippocampus; histopathology; immunocytochemistry; inflammation; interferon gamma; laboratory mouse; model design /development; neuroimmunomodulation; neurotrophic factors; pathologic process; presenilin; tau proteins

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a neurodegenerative disorder associated with progressive functional decline, dementia and neuronal loss initiated in specific brain regions and progressing by a disease-specific mode. Elucidating the origin(s) of the pathogenic cascade could likely result in the development of novel diagnostic methodologies and potentially stage-specific therapeutics. 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. Our proposal addresses both the role of inflammation temporally and spatially in pathogenesis as well as examines the interplay between vaccination and inflammation to either slow or exacerbate neurodegeneration. We hypothesize that focal activation of an inflammatory process within the entorhinal cortex of a mouse model of Alzheimer's disease will lead to the exacerbated stepwise propagation of AD-like pathology within the hippocampus and measurable changes in inflammatory mediator transcript levels in the central nervous system. Moreover, peripheral administration of an ABeta-based vaccine delivered via an HSV amplicon vector will attenuate these histological and biochemical and electrophysiological outcomes in a manner dependent upon the form of the delivered immunogen. We propose to create a novel anatomically and temporally controlled inflammation mouse model, that when combined with an established mouse model of Alzheimer's disease, will be utilized to elucidate the role of brain inflammation in propagation of AD-related pathogenesis and how peripheral vaccination modulates this process. Quantitative bionomic technologies will be used in parallel with standard histochemical, biochemical and electrophysiological assays to correlate the molecular mechanisms by which inflammation influences the initiation and propagation of AD-like pathology and degradation of hippocampal-associated synapses.

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，与进行性功能下降、痴呆和神经元丢失相关，在特定脑区开始，并以疾病特异性模式进展。阐明致病级联的起源可能会导致新的诊断方法和潜在的阶段特异性治疗的发展。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。我们的建议解决了炎症在发病机制中的时间和空间作用，并检查了疫苗接种和炎症之间的相互作用，以减缓或加剧神经退行性变。我们假设阿尔茨海默病小鼠模型内嗅皮层内炎症过程的局灶性激活将导致海马内AD样病理学的逐步传播加剧，并导致中枢神经系统中炎症介质转录水平的可测量变化。此外，通过HSV扩增子载体递送的基于A β的疫苗的外周施用将以依赖于递送的免疫原的形式的方式减弱这些组织学和生物化学和电生理学结果。我们建议创建一种新的解剖学和时间控制的炎症小鼠模型，当与已建立的阿尔茨海默病小鼠模型相结合时，将被用来阐明脑炎症在AD相关发病机制传播中的作用以及外周疫苗接种如何调节这一过程。定量生物学技术将与标准组织化学、生物化学和电生理学测定平行使用，以关联炎症影响AD样病理的起始和传播以及突触相关突触降解的分子机制。