Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, of which the pathogenesis is thought to involve increased beta-amyloid (Abeta) deposition and abnormal immunological responses. To elucidate the mechanisms involved in Abeta-mediated inflammation, we used immunocytochemistry and in situ hybridization to study the potential role of the cytokines interferon-gamma (IFN-gamma), interleukin (IL)-12 and IL-4 in transgenic mice APP(SWE) (Tg2576) that overexpress the human beta-amyloid precursor protein gene. Cytokine and cytokine mRNA expression was detected in brain sections from cortical regions at various postnatal ages ranging from 3 to 19 months. High levels of IFN-beta and IL-12 mRNA expression, as well as their protein production, appeared early at 9 months and peaked at 17-19 months ill Tg2576 mice. Significantly increased transcripts of IFN-gamma and IL-12 genes were found in the reactive microglia and astrocytes surrounding beta-amyloid deposits. In accordance with the kinetics of mRNA levels, the expression of IFN-gamma and IL-12 at the protein level was positively correlated with age and reached a maximum in 17-19-month-old mice. Both findings suggest a role for the pro-inflammatory cytokines IFN-gamma and IL12 in early disease development and are consistent with microglial activation related to beta-amyloid formation. In contrast, transcription and production of IL-4 in brain sections was almost undetectable in transgenic mice up to post-natal ages of 17- 19 months. These results suggest a major pro-inflammatory role for IL-12 and IFN-gamma in Tg2576 transgenic mice that may provide the association between beta-amyloid plaque formation and microglial and astrocyte activation in these animals. These observations call for further studies on the potential role of antiflammatory therapeutic strategies for AD. (C) 2002 Elsevier Science B.V All rights reserved.