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 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 (Abeta), 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 Abeta 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 Abeta: alpha1-antichymotrypsin (ACT), interleukin-1beta (IL-1beta), S100beta, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Abeta to activate astrocytes. Treatment of astrocytes with ACT, IL-1beta, or S100beta resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1beta, and production of inducible nitric oxide synthase and nitric oxide. The ability of Abeta 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 Abeta-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 Abeta-induced activation.
Hu
J
J
Department of Cell and Molecular Biology, Ward 4-202, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USA.
Van Eldik
L J
LJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D015153:Blotting, Western; D002091:Butyrylcholinesterase / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects; D002478:Cells, Cultured; D007375:Interleukin-1 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D009566:Nitrates / Q000378:metabolism; D051381:Rats; D009418:S100 Proteins / Q000494:pharmacology; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D009566:Nitrates; D009418:S100 Proteins; D000514:alpha 1-Antichymotrypsin; D002091:Butyrylcholinesterase