We have previously shown that amyloid- (A) 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 on endogenous apoE and apoJ levels, and the potential role of apoE receptors in astrocyte activation have not been addressed. Three activating stimuli (lipopolysaccharide (LPS), dibutyryl (db) cAMP, and aged A-beta1-42) were used to induce activation of rat astrocyte cultures, as assessed by changes in morphology and an increase in interleukin-1. However, onlyA-beta also induced ~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 (RAP), 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, while LDLR mediates the A-induced changes in apoE levels. RAP had no effect on apoJ levels, or on activation by either dbcAMP or LPS. 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.
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