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PMID: 16554485 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta peptide 1-40.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 26 ·No. 12 ·2006-03-22 ·Pages 3345-56

Qin S, Colin C, Hinners I, Gervais A, Cheret C, Mallat M

Abstract

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.

MeSH Terms
Alzheimer Disease/metabolism,physiopathology Amino Acid Transport System y+/genetics,metabolism Amyloid beta-Peptides/toxicity Animals Apolipoproteins E/genetics,metabolism Cell Communication/physiology Cell Death/drug effects,physiology Cell Survival/drug effects,physiology Cells, Cultured Coculture Techniques Female Gene Expression Regulation/drug effects,physiology Glutamic Acid/metabolism Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microglia/metabolism Nerve Degeneration/metabolism,physiopathology Neurons/drug effects,metabolism,pathology Peptide Fragments/toxicity Rats Rats, Wistar
Chemicals
Amino Acid Transport System y+ Amyloid beta-Peptides Apolipoproteins E Peptide Fragments Slc7a11 protein, mouse amyloid beta-protein (1-40) Glutamic Acid
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Qin Si
Institut National de la Santé et de la Recherche Médicale Unité 711, 75651 Paris Cedex 13, France.
Colin Catherine
Hinners Ina
Gervais Annie
Cheret Cyril
Mallat Michel
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.5186-05.2006
Published
2006-03-22
Pages
3345-56
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6674113
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.5186-05.2006 PMC Full Text View journal details
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