title: Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice.
abstract: 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-gamma 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-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 IL-12 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 anti-inflammatory therapeutic strategies for AD.
authors.affiliation: Division of Geriatric Medicine (B84), Karolinska Institute, Huddinge University Hospital, S-141 86 Stockholm, Sweden.
authors.forename: Nagat
authors.initials: N
authors.lastname: Abbas
authors.forename: Ivan
authors.initials: I
authors.lastname: Bednar
authors.forename: Eilhard
authors.initials: E
authors.lastname: Mix
authors.forename: Svedberg
authors.initials: S
authors.lastname: Marie
authors.forename: David
authors.initials: D
authors.lastname: Paterson
authors.forename: Anna
authors.initials: A
authors.lastname: Ljungberg
authors.forename: Chris
authors.initials: C
authors.lastname: Morris
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002540:Cerebral Cortex / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma