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 β (Aβ) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the Aβ precursor protein (APP), promoting further Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ in young Tg2576 mice. These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Aβ 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 Aβ deposition in vivo.