Cu(II) enhances the effect of Alzheimer’s amyloid-β peptide on microglial activation

Journal of Neuroinflammation

Juan Li¹  Hongzhuan Chen¹  Xiaoling Gao¹  Yongyao Cui¹  Yu Qiu¹  Zhuqin Hu²  Ping Gong¹  Fengxiang Yu¹ 

[1]Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China

[2]Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China

关键词: NF-кB;    Nitric oxide;    Tumor necrosis factor-α;    Reactive oxygen species;    Microglia;    Aggregation;    Cu(II)-Aβ complex;   

Others  :  1221949
DOI  :  10.1186/s12974-015-0343-3

 received in 2014-12-26, accepted in 2015-06-12,  发布年份 2015

【 摘 要 】

Background

Aggregated forms of amyloid-β (Aβ) peptides are important triggers for microglial activation, which is an important pathological component in the brains of Alzheimer’s patients. Cu(II) ions are reported to be coordinated to monomeric Aβ, drive Aβ aggregation, and potentiate Aβ neurotoxicity. Here we investigated whether Cu(II) binding modulates the effect of Aβ on microglial activation and the subsequent neurotoxicity.

Methods

Aβ peptides were incubated with Cu(II) at an equimolar ratio to obtain the Cu(II)-Aβ complex. Primary and BV-2 microglial cells were treated with Cu(II)-Aβ, Aβ, or Cu(II). The tumor necrosis factor-α (TNF-α) and nitric oxide levels in the media were determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was detected by MitoSOX oxidation.

Results

Incubation of Cu(II) with Aβ confers different chemical properties on the resulting complex. At the subneurotoxic concentrations, Cu(II)-Aβ (but not Aβ or Cu(II) alone) treatment induced an activating morphological phenotype of microglia and induced the microglial release of TNF-α and nitric oxide as well as microglia-mediated neuronal damage. Cu(II)-Aβ-triggered microglial activation was blocked by nuclear factor (NF)-κB inhibitors and was accompanied with NF-κB activation. Moreover, Cu(II)-Aβ induced hydrogen peroxide release, which was not affected by NADPH oxidase inhibitors. Mitochondrial superoxide production was increased after Cu(II)-Aβ stimulation. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), inhibited Cu(II)-Aβ-elicited microglial release of TNF-α and nitric oxide as well as the microglia-mediated neurotoxic effect.

Conclusion

Our observations suggest that Cu(II) enhances the effect of Aβ on microglial activation and the subsequent neurotoxicity. The Cu(II)-Aβ-triggered microglial activation involves NF-κB activation and mitochondrial ROS production.

【 授权许可】

   
2015 Yu et al.

【 图 表 】

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