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System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta
Si Qin1, Catherine Colin, Ina Hinners
1Institut National de la Santé et de la Recherche Médicale Unité 711, 75651 Paris Cedex 13, France.
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.
Insights
Microglia worsen amyloid-beta (Abeta) toxicity in Alzheimer's disease (AD) by releasing glutamate. Inhibiting this pathway may offer therapeutic benefits by preventing excitotoxicity and enhancing neuroprotection from apolipoprotein E (apoE).
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) pathology involves amyloid-beta (Abeta) plaques and reactive microglia.
- Microglia's role in Abeta-induced neurotoxicity is complex and not fully understood.
Purpose of the Study:
- To investigate how microglia influence neuronal viability when exposed to aggregated Abeta.
- To elucidate the mechanisms by which microglia modulate Abeta toxicity and neuroprotection.
Main Methods:
- Primary rodent neuronal cultures exposed to aggregated Abeta 1-40.
- Assessment of microglial influence on neuronal viability.
- Analysis of glutamate release via system Xc- and NMDA receptor involvement.
- Investigation of apolipoprotein E (apoE) mediated neuroprotection by microglia.
Main Results:
- Microglia enhanced Abeta neurotoxicity by releasing glutamate through the cystine-glutamate antiporter system Xc-.
- System Xc- and NMDA receptor inhibition prevented microglial-enhanced Abeta toxicity.
- Microglia also exhibited neuroprotective effects mediated by secreted apolipoprotein E (apoE).
- Inhibition of microglial system Xc- prevented glutamate excitotoxicity and facilitated apoE-mediated neuroprotection.
Conclusions:
- Microglial system Xc- activity contributes to Abeta-induced neurotoxicity in Alzheimer's disease.
- Inhibiting microglial system Xc- may be a therapeutic strategy for AD.
- This inhibition could mitigate excitotoxicity while preserving microglial-mediated neuroprotection via apoE.
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