title: Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition.
abstract: Proinflammatory stimuli, after amyloid beta (Abeta) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the Abeta precursor protein (APP), promoting further Abeta accumulation and neuroinflammation in Alzheimer's disease (AD). Interleukin-6 (IL-6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction. To assess the effects of IL-6 on Abeta deposition and APP processing in vivo, we overexpressed murine IL-6 (mIL-6) in the brains of APP transgenic TgCRND8 and TG2576 mice. mIL-6 expression resulted in extensive gliosis and concurrently attenuated Abeta deposition in TgCRND8 mouse brains. This was accompanied by up-regulation of glial phagocytic markers in vivo and resulted in enhanced microglia-mediated phagocytosis of Abeta aggregates in vitro. Further, mIL-6-induced neuroinflammation had no effect on APP processing in TgCRND8 and had no effect on APP processing or steady-state levels of Abeta in young Tg2576 mice. These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Abeta plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology. This is the first study that methodically dissects the contribution of mIL-6 with regard to its potential role in modulating Abeta deposition in vivo.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.forename: Amanda
authors.initials: A
authors.lastname: Beccard
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.forename: Christophe
authors.initials: C
authors.lastname: Verbeeck
authors.forename: Abba C
authors.initials: AC
authors.lastname: Zubair
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015850:Interleukin-6