Cytokine Modulation of AB Associated Pathologies in Mouse Models of AD

描述(申请人提供)：大脑中的慢性炎症反应，已被认为与年龄相关的神经退行性疾病有关，如阿尔茨海默病(AD)。在阿尔茨海默病中，脑内神经胶质细胞在A？沉积后被神经胶质细胞表面的天然免疫受体激活，导致神经胶质细胞活化、表型转化和释放可溶性炎症介质。其中一些炎性介质可以直接对神经元产生毒性，因此它们被指责为导致神经退行性变的原因。此外，在AD的情况下，假设这些炎性细胞因子可能会改变APP的处理和A？清除机制，创建“反馈循环”，促进A？的进一步积累。然而，我们现在已经产生了大量的数据表明，炎性细胞因子(例如，IL-6、IFN3和TNF1)的过度表达不会显著改变体内APP水平、APP处理或稳定的A？代。相反，所有三种炎性细胞因子都有一个有益的效果，即，当它们在疾病过程的早期表达时，它们显著地“减少”淀粉样蛋白的沉积，而当它们在先前存在显著的淀粉样蛋白负担的老年小鼠中表达时，对淀粉样蛋白的沉积没有影响(既不增加也不减少)。相反，AAV介导的抗炎细胞因子IL-10的过度表达导致APP转基因小鼠淀粉样蛋白沉积显著增加，并加剧了认知障碍(详细信息见特定目标2)。因此，根据时间和背景的不同，单个细胞因子的作用可能在疾病过程中产生不同的和意想不到的影响。现在越来越多的证据表明，大脑中的神经免疫相互作用是错综复杂的，并参与了显著的串扰，以维持大脑的动态平衡和保护大脑。在阿尔茨海默病中，这些复杂的神经-神经胶质相互作用和免疫反应在大脑中的作用在很大程度上尚未解决。在这个方案中，我们将利用我们的AAV系统来探索单个细胞因子和趋化因子的影响，特别是当它与AD相关的病理学相关时。这项提案中概述的研究将深入了解特定的神经炎症和神经调节反应如何影响淀粉样蛋白沉积和微管相关蛋白tau病理，这是AD的两个标志性病理特征。 公共卫生相关性：这项研究将使用阿尔茨海默病(AD)的小鼠模型来系统地评估神经免疫反应在AD大脑中的作用。这些研究将深入了解炎症在AD病理中的作用，并可能导致开发治疗AD的新的治疗方法。

DESCRIPTION (provided by applicant): Chronic inflammatory reactions in the brain, has been implicated to play a role in age-related neurodegenerative disorder's, such as Alzheimer's disease (AD). In AD, glial cells in the brain are alerted by the innate immune receptors on the glial cell surface following A¿ deposition, resulting in activation, phenotypic transformation and release of soluble inflammatory mediators by the glial cells. Some of these inflammatory mediators can be directly toxic to neurons and therefore they have been accused in driving neurodegeneration. Furthermore, in the case of AD, it is hypothesized that these inflammatory cytokines can potentially alter APP processing and A¿ clearance mechanisms, creating "feedback loops", that promote further A¿ accumulation. However, we have now generated a wealth of data suggesting that over-expression of inflammatory cytokines (e.g., IL-6, IFN3 and TNF1) does not significantly alter APP levels, APP processing or steady state A¿ generation in vivo. Rather, all three inflammatory cytokines have a beneficial effect, i.e., they significantly "attenuate" amyloid deposition when expressed early in the disease process and have no effect (neither increase nor decrease) on amyloid deposition when expressed in older mice with significant pre-existing amyloid burdens. In contrast, AAV mediated over-expression of anti-inflammatory cytokine IL-10 led to significantly increased amyloid deposition and exacerbated cognitive deficits in APP transgenic mice (details in Specific Aim 2). Thus, depending on the timing and context, the actions of individual cytokines may produce divergent and unexpected effects during the disease process. Growing evidence now suggests that neural- immune interactions in the brain are intricately connected, complex and engage in significant crosstalk to maintain brain homeostasis and protect the brain. In AD, the role of these complex neural-glial interactions and immune responses in the brain are largely unresolved. In this proposal, we will take advantage of our AAV system to explore the effects of individual cytokines and chemokines particularly as it relates to AD-associated pathologies. The studies outlined in this proposal will provide insight into how specific neuro-inflammatory and neuro-modulatory reactions affect amyloid deposition and microtubule -associated protein tau pathology, the two hallmark pathological features of AD. PUBLIC HEALTH RELEVANCE: This study will use mouse models of Alzheimer's disease (AD) to systematically evaluate the role of the neural- immune responses in AD brain. These studies will provide insight into the role of inflammation on AD pathologies, and potentially lead to the development of novel therapeutic approaches for treating AD.