Modulating Disease in Alzheimer's Disease Models

描述（由申请人提供）：阿尔茨海默病（AD）的特征是智力和情感功能的恶化，85岁以上的患者中有40%患有此病。阿尔茨海默病的病理标志包括淀粉样蛋白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起关键作用，具有时间和空间的演化特征。我们感兴趣的是了解导致或延续这种AD发病机制的时间和空间进展的早期机制。最近，一个三重转基因（3xTg-AD）的阿尔茨海默病小鼠模型已经建立，同时发生淀粉样蛋白和tau蛋白病理，这是迄今为止描述人类阿尔茨海默病发生的最好的模型系统。我们发现在淀粉样蛋白病理之前，该模型中TNF-a的显著上调，并希望研究该细胞因子在早期疾病中的作用。我们假设TNF-a介导的炎症使AD模型中存在淀粉样蛋白和棕褐色蛋白病变的遗传易感性，并且抑制这种炎症反应将减少病理性淀粉样蛋白和tau蛋白的结果。此外，我们假设炎症事件发生前的局灶性诱导将以区域和时间的方式加剧病理结果。我们将使用表达TNF-a的重组腺相关病毒（rAAV）载体来产生持续的炎症反应或TNF受体拮抗剂来抑制现有病理之前的内源性炎症反应。这项工作将使我们对炎症参与早期阿尔茨海默病致病事件的时间和空间进展有重要的了解，并可能提供新的治疗靶点。

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is characterized by deterioration of intellectual and emotional functioning, afflicting 40% of those over 85. Pathological hallmarks of the disease include amyloid beta (AB) plaques and neurofibrillary tangles, which play a key role in the pathogenic mechanism of AD, 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. Recently, a triple transgenic (3xTg-AD) mouse model of AD that develops both amyloid and tau pathology has been created, which to date is the best model system depicting what occurs in human AD. We have found significant upregulation of TNF-a in this model prior to amyloid pathology and want to investigate the role of this cytokine in early disease. We hypothesize that TNF-a mediate inflammation perpetuates disease in an AD model where genetic predisposition to amyloid and tan 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 foe inflammatory response or a TNF receptor antagonist to inhibit the endogenous inflammatory response prior to existing pathology. This work will give us major insight on the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially provide a new therapeutic target.