Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation

A prominent feature of Alzheimer's disease (AD) pathology is an abundance o f activated glia (astrocytes and microglia) in close proximity to the amylo id plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of i nflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 ( A beta), a major constituent of neuritic plaques, can itself induce glial a ctivation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or m odulate the effects of A beta on glia. In this study, we focused on four gl ial proteins that are abundant in amyloid plaques and/or that are known to interact with A beta: alpha 1-antichymotrypsin (ACT), interleukin-1 beta (I L-1 beta), S100 beta and butyrylcholinesterase (BChE). We examined the abil ity of these proteins to activate rat cortical astrocyte cultures and to in fluence the ability of A beta to activate astrocytes. Treatment of astrocyt es with ACT, IL-1 beta, or S100 beta resulted in glial activation, as asses sed by reactive morphology, upregulation of IL-1 beta, and production of in ducible nitric oxide synthase and nitric oxide. The ability of A beta to in duce astrocyte activation was also enhanced in the presence of each of thes e three proteins. In contrast, BChE alone did not activate astrocytes and h ad no effect on A beta-induced activation. These results suggest that certa in proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directl y or through their ability to modulate A beta-induced activation. (C) 1999 Elsevier Science B.V. All rights reserved.