IL-1 mediated activation of innate immunity underlies Alzheimer plaque clearance

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DESCRIPTION (provided by applicant): Neuroinflammation is a local tissue response to injurious stimuli in the central nervous system (CNS) and is characterized by glial reactivity, induction of cytokines and chemokines and vascular permeability. It may also involve recruitment of peripheral immune cells. A key player in this response is the proinflammatory cytokine interleukin(IL)-1?. IL-1 is rapidly induced in microglia following acute CNS injury or insult, and may be chronically overexpressed in conditions where continuous or repeated harmful stimuli are present, such as in neurodegenerative disorders like Alzheimer's disease (AD). For this reason, IL-1 has long been thought to promote neurodegeneration. Previous work in this lab utilized a novel model of sustained IL-1 production in the brain in conjunction with a mouse model of AD to study the link between IL-1 and AD pathogenesis. This model exhibits a spatially and temporally controlled IL-1 dependent neuroinflammatory response that significantly reduced plaque pathology in the APPswe/PS1 Alzheimer's mouse. Importantly, preliminary work identified increased numbers of microglia surrounding amyloid-? plaques in the IL-1 overexpressing animals. To better characterize the role of endogenous IL-1 in AD pathogenesis, we will quantify endogenous IL-1 expression over a timecourse of plaque development in the APP/PS1 mouse. In order to solidify the link between chronic expression of IL-1 and amyloid clearance, additional studies will employ transgenic and viral vector approaches to achieve sustained upregulation of IL-1 signaling and analyze various AD pathological features. Furthermore, we hypothesize that IL-1 induces microglial-mediated plaque clearance through induction of the innate immune response. This is supported by significant elevation of MCP-1 and increased numbers of microglia surrounding amyloid plaques in our model. To study whether monocytic recruitment from the periphery is responsible for the observed cellular increases, we aim to modify cellular recruitment to the hippocampus during sustained IL-1? expression. Similar methods will be employed to determine whether bone-marrow derived microglia play a role in the observed plaque clearance. Our proposed studies will help to elucidate the role of brain inflammation in neurodegenerative disorders. This is critical since inflammation has been proposed as a therapeutic target in these diseases. Alzheimer's disease is a major public health challenge in our aging society and steps taken to better understand how it develops may lead to new therapies or methods to prevent disease.