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

Abstract

A prominent feature of Alzheimer's disease (AD) pathology is an abundance of activated glia (astrocytes and microglia) in close proximity to the amyloid plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of inflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 (Aβ), a major constituent of neuritic plaques, can itself induce glial activation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or modulate the effects of Aβ on glia. In this study, we focused on four glial proteins that are abundant in amyloid plaques and/or that are known to interact with Aβ: α1-antichymotrypsin (ACT), interleukin-1β (IL-1β), S100β, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Aβ to activate astrocytes. Treatment of astrocytes with ACT, IL-1β, or S100β resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1β, and production of inducible nitric oxide synthase and nitric oxide. The ability of Aβ to induce astrocyte activation was also enhanced in the presence of each of these three proteins. In contrast, BChE alone did not activate astrocytes and had no effect on Aβ-induced activation. These results suggest that certain proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directly or through their ability to modulate Aβ-induced activation.