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Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition

2009; Wiley; Volume: 24; Issue: 2 Linguagem: Inglês

10.1096/fj.09-141754

1530-6860

Paramita Chakrabarty, Karen Jansen‐West, Amanda Beccard, Carolina Ceballos‐Diaz, Yona Levites, Christophe Verbeeck, Abba C. Zubair, Dennis W. Dickson, Todd E. Golde, Pritam Das,

Tryptophan and brain disorders

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.