Interleukin-1: A Mediator of Neuroinflammation and Alzheimer's Neuropathogenesis

描述（由申请人提供）：神经炎症，其特征在于活化的小胶质细胞和星形胶质细胞以及广泛的炎症介质的局部表达，是对脑损伤的基本反应，无论是创伤、中风、感染还是神经变性。这种局部组织反应肯定是修复和恢复过程的一部分。然而，与外周疾病中的许多炎症性疾病一样，神经炎症可以导致中枢神经系统疾病的病理生理学。例如，在阿尔茨海默病（AD）中，传统上认为胶质细胞驱动的炎症反应会促进神经退行性变。然而，最近的数据表明，神经炎症在这种疾病中的作用更为复杂。中枢神经系统炎症的关键参与者之一是促炎细胞因子白细胞介素（1 L）-1，其由活化的小胶质细胞产生，并在AD中升高。该提议的首要假设是IL-1在神经炎症中发挥驱动力，因此对IL-1水平长期升高的阿尔茨海默病具有重大影响。为了验证这一假设，我们开发了几种新的转基因小鼠品系，旨在提供持续和局部表达的IL-1或IL-1 ra，在我们选择的年龄，没有发育补偿，这是经常看到的标准转基因模型。如初步数据所述，IL-1产生的诱导导致深刻和持续的神经炎症反应。结合其他遗传、细胞和药理学方法，这些小鼠的研究应该为IL-1在慢性神经炎性疾病，特别是阿尔茨海默病中的作用提供新的见解。我们的三个目标是：第一，进一步表征与持续IL-1？表达相关的神经炎症变化;第二，使用两种AD小鼠模型探索IL-1？对阿尔茨海默病中存在的神经病理学标志（斑块和缠结）的影响;第三，通过抵消IL-1在这些模型中的作用来补充这些后期的AD神经发病机制研究。这三个目标将提供一个更好的理解IL-1的作用，在AD和神经炎症在体内设置。这些信息直接说明了用于治疗和预防阿尔茨海默病的免疫调节疗法的开发和实施，阿尔茨海默病是我们老龄化社会的一项重大公共卫生挑战。

DESCRIPTION (provided by applicant): Neuroinflammation, characterized by activated microglia and astrocytes and local expression of a wide range of inflammatory mediators, is a fundamental reaction to brain injury, whether by trauma, stroke, infection, or neurodegeneration. This local tissue response is surely part of a repair and restorative process. Yet, like many inflammatory conditions in peripheral diseases, neuroinflammation can contribute to the pathophysiology of CNS disorders. For example, in Alzheimer's disease (AD), glial-driven inflammatory responses to A¿ deposition are traditionally thought to promote neurodegeneration. However, more recent data suggests a more complex picture for the role of neuroinflammation in this disease. One of the key players in CNS inflammation is the proinflammatory cytokine interleukin (1L)-1¿, which is produced by activated microglia and is found elevated in AD. The overriding hypothesis for this proposal is that IL-1 plays a driving force in neuroinflammation and as such, has significant impact in Alzheimer's disease where IL-1 levels are chronically elevated. In order to test this hypothesis, we have developed several new transgenic mouse lines designed to provide sustained and localized expression of IL-1¿ or IL-1ra, at an age of our choosing, and without developmental compensation that is often seen in standard transgenic models. As described in preliminary data, induction of IL-1 production leads to a profound and sustained neuroinflammatory response. Combined with other genetic, cellular, and pharmacological approaches the studies proposed with these mice should provide new insight into the role of IL-1 in chronic neuroinflammatory disorders, particularly Alzheimer's disease. Our three aims are first, to further characterize the neuroinflammatory changes associated with sustained IL-1¿ expression; second, to explore the effects of IL-1¿ on neuropathological hallmarks present in Alzheimer's disease (both plaques and tangles) using two AD mouse models; and third, to complement these later studies of AD neuropathogenesis by counteracting IL-1's actions in these models. Together these three aims will provide a better understanding of IL-1's role in AD and neuroinflammation in an in vivo setting. Such information speaks directly to the development and implementation of immunomodulatory therapies for the treatment and prevention of Alzheimer's disease, a major public health challenge for our aging society.