System Xc−and Apolipoprotein E Expressed by Microglia Have Opposite Effects on the Neurotoxicity of Amyloid-β Peptide 1–40
Open accessAbstract
Because senile plaques in Alzheimer's 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.
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Microglia release O2− or O2−-derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases.
“release O 2 ⅐Ϫ or O 2 ⅐Ϫ -derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases (Sankarapandi et al., 1998;Zhang et al., 2005;B. Qin et al., 2006;Wilkinson et al., 2006).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as B. Qin et al., 2006
The Discussion (page unavailable) reports superoxide production by amyloid-β-stimulated microglia and refers to free-radical-producing microglia activated by amyloid-β or LPS. Our copy does not establish release of hydrogen peroxide or address opsonized zymosan, so it supports only part of the sentence. (LLM, conf=0.84)
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- Authors
- Qin, S., Colin, C., Hinners, I., Gervais, A., Cheret, C., & Mallat, M.
- Affiliations
- Inserm (FR)
- Corresponding author
- Mallat, Michel
- ORCID
- Mallat, Michel
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-03-22
- Volume
- 26
- Issue
- 12
- Pages
- 3345-3356
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674113
- OpenAlex
- W1963882244
- Cited by
- 135
- References
- 8
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 1 · 2018: 7 · 2017: 4 · 2016: 6 · 2015: 13 · 2014: 7 · 2013: 13 · 2012: 11
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sanofi
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- system xc-, SLC7A11, apolipoprotein E, microglia, Aβ40, Alzheimer's disease, neurotoxicity, glutamate excitotoxicity, NMDA receptor, neuroprotection, amyloid plaques, APOE isoforms
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Cell Communication, Cell Survival, Cells, Cultured, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Peptide Fragments, Amyloid beta-Peptides, Cell Death, Rats, Wistar, Microglia, Mice, Knockout, Glutamic Acid, Coculture Techniques, Amino Acid Transport System y+, Mice, Rats
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