Proinflammatory stimuli are needed for induction of microglial cell-mediated A beta PP244-C and A beta-neurotoxicity in hippocampal cultures

Abstract

Amyloid-beta 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-beta- and amyloid-beta 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-beta or amyloid-beta protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1 beta. 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 beta 1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor beta 1 by inflammation plus amyloid-beta and amyloid-beta protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-beta or amyloid-beta 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 1 beta and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor beta 1 support persistent activation of glial cells and cell damage.