Modulating Disease in Alzheimer's Disease Models

描述(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，在85岁以上的人中有40%受到困扰。该病的病理特征包括淀粉样β蛋白(AB)斑块和神经原纤维缠结，它们在AD的发病机制中发挥关键作用，并在时间和空间上演变。我们感兴趣的是了解导致或维持AD发病的这种时间和空间进展的早期机制。最近，一个同时发生淀粉样蛋白和tau病变的三重转基因(3xTg-AD)小鼠模型已经建立，这是迄今为止描述人类AD发生的最好的模型系统。我们发现，在淀粉样蛋白病理之前，该模型中肿瘤坏死因子-α显著上调，并希望研究这种细胞因子在早期疾病中的作用。我们假设，在AD模型中，肿瘤坏死因子-α介导的炎症使疾病持续存在，其中存在淀粉样蛋白和黄褐色病变的遗传易感性，并且抑制这种炎症反应将减少病理淀粉样蛋白和tau蛋白的结果。此外，我们假设在炎症发生之前局部诱发炎症事件会以区域性和暂时性的方式加重病理结果。我们将应用表达肿瘤坏死因子-a的重组腺相关病毒(RAAV)载体，以产生持续的炎症反应，或应用肿瘤坏死因子受体拮抗剂，在现有病理之前抑制内源性炎症反应。这项工作将使我们深入了解炎症在早期AD致病事件的时间和空间进展中的作用，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.