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

描述(申请人提供)：神经炎，以激活的小胶质细胞和星形胶质细胞为特征，局部表达广泛的炎症介质，是对脑损伤的基本反应，无论是由创伤、中风、感染或神经变性引起的。这种局部组织反应肯定是修复和恢复过程的一部分。然而，就像周围疾病中的许多炎症性疾病一样，神经炎症可以促进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，神经胶质细胞对A？沉积的炎症反应传统上被认为会促进神经退化。然而，最近的数据表明，神经炎症在这种疾病中的作用有更复杂的图景。中枢神经系统炎症的关键因素之一是促炎细胞因子白介素1，它是由激活的小胶质细胞产生的，在AD中发现升高。这一提议的压倒一切的假设是，IL-1在神经炎症中发挥推动作用，因此，在IL-1水平长期升高的阿尔茨海默病中具有重大影响。为了验证这一假设，我们开发了几个新的转基因小鼠系，旨在提供持续和局部的IL-1？或IL-1ra的表达，在我们选择的年龄，并且没有标准转基因模型中常见的发育补偿。正如初步数据所描述的，诱导IL-1的产生会导致深刻而持久的神经炎性反应。结合其他遗传学、细胞学和药理学方法，对这些小鼠进行的研究将为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，进一步表征与持续表达IL-1β相关的神经炎性变化；第二，利用两个AD小鼠模型，探讨IL-1β对阿尔茨海默病(包括斑块和缠结)神经病理特征的影响；第三，通过对抗IL-1‘S在这些模型中的作用，补充这些后来关于AD神经发病机制的研究。这三个目标的结合将有助于更好地理解IL-1在体内环境下S在AD和神经炎症中的作用。这些信息直接关系到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.