System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta peptide 1-40.
Because senile plaques in Alzheimer's disease (AD) contain reactive microglia in addition to potentially neurotoxic aggregates of amyloid-beta (Abeta), we examined the influence of microglia on the viability of rodent neurons in culture exposed to aggregated Abeta 1-40. Microglia enhanced the toxicity of Abeta by releasing glutamate through the cystine-glutamate antiporter system Xc-. This may be relevant to Abeta toxicity in AD, because the system Xc(-)-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 Abeta. Inhibition of NMDA receptors or system Xc- prevented the microglia-enhanced neurotoxicity of Abeta 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 Xc- might be of therapeutic value in the treatment of AD. Its inhibition not only prevents glutamate excitotoxicity but also facilitates neuroprotection by apoE.
Institut National de la Santé et de la Recherche Médicale Unité 711, 75651 Paris Cedex 13, France.
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D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D027182:Amino Acid Transport System y+; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C492255:Slc7a11 protein, mouse; C078592:amyloid beta-protein (1-40); D018698:Glutamic Acid