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The Journal of Neuroscience, March 22, 2006, 26(12):3345-3356; doi:10.1523/JNEUROSCI.5186-05.2006

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Neurobiology of Disease
System X_c^– and Apolipoprotein E Expressed by Microglia Have Opposite Effects on the Neurotoxicity of Amyloid- Peptide 1–40

Si Qin,^1,2 Catherine Colin,^1,2 Ina Hinners,^1,2 Annie Gervais,^1,2 Cyril Cheret,^1,2 and Michel Mallat^1,2

¹Institut National de la Santé et de la Recherche Médicale Unité 711, 75651 Paris Cedex 13, France, and ²Université Pierre and Marie Curie, Faculté de médecine Pitié Salpêtrière, Institut Fédératif de Recherche des Neurosciences 70, 75013 Paris, France

Correspondence should be addressed to Michel Mallat, Biologie des Interactions Neurones/Glie, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-711, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. Email: michel.mallat{at}chups.jussieu.fr

Because senile plaques in Alzheimer's disease (AD) contain reactive microglia in addition to potentially neurotoxic aggregates of amyloid- (A), we examined the influence of microglia on the viability of rodent neurons in culture exposed to aggregated A 1–40. Microglia enhanced the toxicity of A by releasing glutamate through the cystine-glutamate antiporter system X_c^–. This may be relevant to A 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 A. Inhibition of NMDA receptors or system X_c^– prevented the microglia-enhanced neurotoxicity of A 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.

Key words: Alzheimer's disease; microglia; NMDA receptor; apolipoprotein E; system X_c^–; neuronal death

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Received Aug. 11, 2005; revised Feb. 2, 2006; accepted Feb. 5, 2006.

Correspondence should be addressed to Michel Mallat, Biologie des Interactions Neurones/Glie, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-711, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. Email: michel.mallat{at}chups.jussieu.fr

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