Beccard, Amanda

Abstract Reactive gliosis surrounding amyloid β (Aβ) plaques is an early feature of Alzheimer’s disease pathogenesis and has been postulated to represent activation of the innate immune system in an apparently ineffective attempt to clear or neutralize Aβ aggregates. To evaluate the role of IFN-γ–mediated neuroinflammation on the evolution of Aβ pathology in transgenic (Tg) mice, we have expressed murine IFN-γ (mIFN-γ) in the brains of Aβ precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-γ in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Aβ deposition. In these mice, mIFN-γ expression upregulated multiple glial activation markers, early components of the complement cascade as well as led to infiltration of Ly-6c positive peripheral monocytes but no significant effects on APP levels, APP processing or steady-state Aβ levels were noticed in vivo. Taken together, these results suggest that mIFN-γ expression in the brain suppresses Aβ accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Aβ aggregate phagocytosis.

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 .—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 Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J . 24, 548–559 (2010). www.fasebj.org