Apolipoprotein E receptors mediate the effects of β-amyloid on astrocyte cultures

We have previously shown that beta -amyloid (A beta) induces astrocyte activation in vitro and that this reaction is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. However, the effects of A beta on endogenous apoE and apoJ levels and the potential role of apoE receptors in astrocyte activation have not been addressed. Three activating stimuli (lipopolysaccharide, dibutyryl cAMP, and aged A beta 1-42) were used to induce activation of rat astrocyte cultures, as assessed by changes in morphology and an increase in interleubin-1 beta. However, only A beta also induced similar to 50% reduction in the amount of released apoE and apoJ and an 8-fold increase in the levels of cell-associated apoE and apoJ, Experiments using two concentrations of receptor-associated protein, an inhibitor of apoE receptors with a differential affinity for the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), suggest that LRP mediates A beta -induced astrocyte activation, whereas LDLR mediates the A beta -induced changes in apoE levels. Receptor-associated protein had no effect on apoJ levels or on activation by either dibutyryl cAMP or lipopolysaccharide. These data suggest that apoE receptors translate the presence of extracellular A beta into cellular responses, both initiating and modulating the inflammatory response induced by A beta.