Novel Mouse Modeling to Dissect AD Pathophysiology

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，与进行性功能衰退、痴呆和神经元丢失有关，起始于特定的大脑区域，以疾病特有的模式发展。阐明致病级联的起源(S)可能会导致新的诊断方法的发展，并可能导致针对不同阶段的治疗。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。我们的建议既解决了炎症在发病机制中的时间和空间作用，也研究了疫苗接种和炎症之间的相互作用，以减缓或加剧神经变性。我们假设，阿尔茨海默病模型小鼠内嗅皮质内炎症过程的局部激活将导致AD样病理在海马区的逐步加剧，并导致中枢神经系统炎症介质转录水平的可测量变化。此外，通过HSV扩增载体递送的ABETA疫苗的外周给药将以依赖于递送的免疫原形式的方式减弱这些组织学、生化和电生理结果。我们建议创建一种新的解剖学和时间可控的炎症小鼠模型，当与已建立的阿尔茨海默病小鼠模型相结合时，将被用于阐明大脑炎症在AD相关发病机制传播中的作用以及外围免疫如何调节这一过程。定量生物学技术将与标准的组织化学、生化和电生理检测并行使用，以关联炎症影响AD样病理的启动和传播以及海马区相关突触退化的分子机制。

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.