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

Proinflammatory stimuli, after amyloid beta (A beta) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the A beta precursor protein (APP), promoting further A beta 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 A beta 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 A beta 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 A beta 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 A beta in young Tg2576 mice. These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing A beta 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 A beta deposition in vivo.-Chakrabarty, P., Jansen-West, K., Beccard, A., Ceballos-Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., Das, P. Massive gliosis induced by interleukin-6 suppresses A beta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548-559 (2010). www.fasebj.org