Macrophage colony stimulatory factor and interferon-γ trigger distinct mechanisms for augmentation of β-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 (fAbeta), 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 (IFNgamma) appears to be required for this fAbeta-induced microglia mediated neurotoxicity in vitro. We report here that while both MCSF and IFNgamma induce microglial-mediated fAbeta neurotoxicity, their mechanisms of toxicity differ. The enhancement of neurotoxicity by IFNgamma or MCSF is not due to enhanced Abeta ingestion by microglia or to the direct effect of proinflammatory cytokine production. The neurotoxicity resulting from IFNgamma/fAbeta 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 IFNgamma-mediated toxicity mechanism. In contrast, no induction of nitric oxide production was detected for microglia treated with MCSF/fAbeta. Furthermore, inhibiting the generation of reactive oxygen species (ROS) using the specific NADPH oxidase inhibitor apocynin reversed fAbeta/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 fAbeta/MCSF coactivated microglia may be a more appropriate model for assessing fAbeta-induced microglial-mediated neuropathology in AD.