IFN-γ Promotes Complement Expression and Attenuates Amyloid Plaque Deposition in Amyloid β Precursor Protein Transgenic Mice

Reactive gliosis surrounding amyloid beta (A beta) 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 A beta aggregates. To evaluate the role of IFN-gamma-mediated neuroinflammation on the evolution of A beta pathology in transgenic (Tg) mice, we have expressed murine IFN-gamma (mIFN-gamma) in the brains of A beta 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 A beta 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 A beta levels, APP processing or steady-state All levels were noticed in vivo. Taken together, these results suggest that mIFN-gamma expression in the brain suppresses A beta accumulation through synergistic effects of activated glia and components of the innate immune system that enhance A beta aggregate phagocytosis. The Journal of Immunology, 2010, 184: 5333-5343.