Abstract
Amyloid-β plaques and neurodegeneration are hallmarks of Alzheimer's disease, where glial cells are responsible for sustained neuroinflammation. Here we show that hippocampal-microglia co-cultures exposed to proinflammatory mediators, amyloid-β- and amyloid-β protein precursor construct-conjugated beads increased their production of nitrites. In contrast, inflammation was unable to significantly induce cell death by itself, whereas inflammation plus amyloid-β or amyloid-β protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1β. Those effects were not observed in the absence of microglia or when hippocampal cells were co-cultured with microglia for one day. In contrast, a 2-fold increase of transforming growth factor β1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor β1 by inflammation plus amyloid-β and amyloid-β protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-β or amyloid-β protein precursor was a slow process depending on activated microglia and additional stimuli. The observed cytotoxicity could be consequence of a vicious cycle in which elevated concentrations of Interleukin 1β and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor β1 support persistent activation of glial cells and cell damage.