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，困扰着40%的85岁以上的人。该疾病的病理学标志包括淀粉样蛋白β（AB）斑块和神经纤维缠结，其在AD的致病机制中起关键作用，以时间和空间方式演变。我们有兴趣了解早期机制，导致或延续这种时空进展的AD发病机制。最近，已经创建了发展淀粉样蛋白和tau病理的AD的三重转基因（3xTg-AD）小鼠模型，其是迄今为止描述在人类AD中发生的情况的最佳模型系统。我们已经发现在淀粉样蛋白病理学之前，该模型中TNF-α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-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棕褐色病理的遗传易感性，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。这项工作将使我们对炎症参与早期AD致病事件的时间和空间进展有重要的了解，并可能提供一个新的治疗靶点。

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.