Abstract
Neuroinflammation, characterized by glial reactivity, vascular permeability, and induction of cytokines and chemokines, is a local tissue response to injurious stimuli in the central nervous system (CNS). A key participant in this response is the proinflammatory cytokine interleukin(IL)-1β, which is rapidly induced in microglia following acute CNS insult and chronically overexpressed in neurodegenerative disorders such as Alzheimer's disease (AD). For this reason, IL-1 has long been thought to promote neurodegeneration. Previously, we crossed a mouse harboring an inducible element for sustained CNS IL-1 production (IL-1XAT) with the APPswe/PS1 Alzheimer's mouse to explore the link between IL-1 and AD pathogenesis. These animals exhibited a spatially and temporally controlled IL-1 dependent neuroinflammatory response that significantly reduced plaque pathology without influencing amyloid production or processing (Shaftel et al., 2007, J. Clin. Invest. 117:1595). Interestingly, we observed increased numbers of activated microglia surrounding amyloid-β plaques in the IL-1 overexpressing animals. To further investigate the association between neuroinflammation and AD pathology, we carried out studies in APPswe/PS1 transgenic mice on a pure C57BL/6 background. Animals were subject to one month or five months of unilateral sustained hippocampal IL-1β expression. To assess whether plaque reduction results from increased numbers of infiltrating peripheral macrophages, bone marrow chimeric animals harboring wild-type or CCR2-/- bone marrow labeled with GFP were also subject to IL-1 overexpression. Both 1 and 5 months after IL-1 induction we observed significant reduction of amyloid deposits in the inflammed hemisphere accompanied by increased numbers of activated microglia surrounding the remaining plaques. Animals receiving wild-type bone marrow showed numerous infiltrating GFP+ cells in the brain parenchyma, many localizing to plaques. The experiment with CCR2-/- bone marrow is still in progress. Our results are consistent with recent evidence that neuroinflammation may play a protective role in Alzheimer's disease and raise concerns about the use of anti-inflammatory therapeutic strategies. Supported by NIH RO1-AG030149 (MKO) and F31-AG031667 (SBM).
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