Macrophage colony stimulatory factor and interferon-gamma trigger distinct mechanisms for augmentation of beta-amyloid-induced microglia-mediated neurotoxicity.
Dysregulated stimulation of microglia, the resident macrophages in the brain, can lead to excessive induction of inflammatory agents and subsequently damage to neurons. Fibrillar beta-amyloid peptide (fA beta), a major component of senile plaques in Alzheimer's disease (AD) brain, is known to induce microglial-mediated neurotoxicity under certain conditions. Microglial 'priming' by macrophage colony stimulatory factor (MCSF) or interferon-gamma (IFN gamma) appears to be required for this fA beta-induced microglia mediated neurotoxicity in vitro. We report here that while both MCSF and IFN gamma induce microglial-mediated fA beta neurotoxicity, their mechanisms of toxicity differ. The enhancement of neurotoxicity by IFN gamma or MCSF is not due to enhanced A beta ingestion by microglia or to the direct effect of proinflammatory cytokine production. The neurotoxicity resulting from IFN gamma/fA beta treatment was blocked by pretreatment with nitric oxide synthase inhibitor L-N-5-(1-iminoethyl) ornithine hydrochloride (L-NIO), consistent with a role for nitric oxide in the IFN gamma-mediated toxicity mechanism. In contrast, no induction of nitric oxide production was detected for microglia treated with MCSF/fA beta. Furthermore, inhibiting the generation of reactive oxygen species (ROS) using the specific NADPH oxidase inhibitor apocynin reversed fA beta/MCSF-induced neurotoxicity while L-NIO had little effect. As MCSF is endogenously expressed within the brain, and both its level and that of the MCSF receptor are dramatically increased in the AD brain, the neurotoxicity resulting from ROS release by fA beta/MCSF coactivated microglia may be a more appropriate model for assessing fA beta-induced microglial-mediated neuropathology in AD.
Li
M
M
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Pisalyaput
K
K
Galvan
M
M
Tenner
A J
AJ
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016207:Cytokines; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma