System Xc− and Apolipoprotein E Expressed by Microglia Have Opposite Effects on the Neurotoxicity of Amyloid-β Peptide 1–40

Because senile plaques in Alzheimer9s disease (AD) contain reactive microglia in addition to potentially neurotoxic aggregates of amyloid-β (Aβ), we examined the influence of microglia on the viability of rodent neurons in culture exposed to aggregated Aβ 1–40. Microglia enhanced the toxicity of Aβ by releasing glutamate through the cystine-glutamate antiporter system X c − . This may be relevant to Aβ toxicity in AD, because the system X c − -specific xCT gene is expressed not only in cultured microglia but also in reactive microglia within or surrounding amyloid plaques in transgenic mice expressing mutant human amyloid precursor protein or in wild-type mice injected with Aβ. Inhibition of NMDA receptors or system X c − prevented the microglia-enhanced neurotoxicity of Aβ but also unmasked a neuroprotective effect of microglia mediated by microglial secretion of apolipoprotein E (apoE) in the culture medium. Immunodepletion of apoE or targeted inactivation of the apoE gene in microglia abrogated neuroprotection by microglial conditioned medium, whereas supplementation by human apoE isoforms restored protection, which was potentiated by the presence of microglia-derived cofactors. These results suggest that inhibition of microglial system X c − might be of therapeutic value in the treatment of AD. Its inhibition not only prevents glutamate excitotoxicity but also facilitates neuroprotection by apoE.