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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, of which the pathogenesis is thought to involve increased β-amyloid (Aβ) deposition and abnormal immunological responses. To elucidate the mechanisms involved in Aβ-mediated inflammation, we used immunocytochemistry and in situ hybridization to study the potential role of the cytokines interferon-γ (IFN-γ), interleukin (IL)-12 and IL-4 in transgenic mice APP SWE (Tg2576) that overexpress the human β-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-γ and IL-12 mRNA expression, as well as their protein production, appeared early at 9 months and peaked at 17–19 months in Tg2576 mice. Significantly increased transcripts of IFN-γ and IL-12 genes were found in the reactive microglia and astrocytes surrounding β-amyloid deposits. In accordance with the kinetics of mRNA levels, the expression of IFN-γ 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-γ and IL-12 in early disease development and are consistent with microglial activation related to β-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-γ in Tg2576 transgenic mice that may provide the association between β-amyloid plaque formation and microglial and astrocyte activation in these animals. These observations call for further studies on the potential role of anti-inflammatory therapeutic strategies for AD.