IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice.

Reactive gliosis surrounding amyloid beta (Abeta) 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 Abeta aggregates. To evaluate the role of IFN-gamma-mediated neuroinflammation on the evolution of Abeta pathology in transgenic (Tg) mice, we have expressed murine IFN-gamma (mIFN-gamma) in the brains of Abeta precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-gamma in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Abeta deposition. In these mice, mIFN-gamma 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 Abeta levels were noticed in vivo. Taken together, these results suggest that mIFN-gamma expression in the brain suppresses Abeta accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Abeta aggregate phagocytosis.