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. ? ? ?
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