Cu enhances the effect of Alzheimer's amyloid-[beta] peptide on microglial activation

• Published in: Journal of neuroinflammation Vol. 12
• Main Authors: Yu, Fengxiang, Gong, Ping, Hu, Zhuqin, Qiu, Yu, Cui, Yongyao, Gao, Xiaoling, Chen, Hongzhuan, Li, Juan
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 24.06.2015
• Subjects: Alzheimer's disease; Care and treatment; Chemical properties; Complications and side effects; Cysteine; Hydrogen peroxide; Nitric oxide; Oxidases; Peptides; Superoxide; Tumor necrosis factor
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-015-0343-3

Background Aggregated forms of amyloid-[beta] (A[beta]) 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 A[beta], drive A[beta] aggregation, and potentiate A[beta] neurotoxicity. Here we investigated whether Cu(II) binding modulates the effect of A[beta] on microglial activation and the subsequent neurotoxicity. Methods A[beta] peptides were incubated with Cu(II) at an equimolar ratio to obtain the Cu(II)-A[beta] complex. Primary and BV-2 microglial cells were treated with Cu(II)-A[beta], A[beta], or Cu(II). The tumor necrosis factor-[alpha] (TNF-[alpha]) 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 A[beta] confers different chemical properties on the resulting complex. At the subneurotoxic concentrations, Cu(II)-A[beta] (but not A[beta] or Cu(II) alone) treatment induced an activating morphological phenotype of microglia and induced the microglial release of TNF-[alpha] and nitric oxide as well as microglia-mediated neuronal damage. Cu(II)-A[beta]-triggered microglial activation was blocked by nuclear factor (NF)-κB inhibitors and was accompanied with NF-κB activation. Moreover, Cu(II)-A[beta] induced hydrogen peroxide release, which was not affected by NADPH oxidase inhibitors. Mitochondrial superoxide production was increased after Cu(II)-A[beta] stimulation. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), inhibited Cu(II)-A[beta]-elicited microglial release of TNF-[alpha] and nitric oxide as well as the microglia-mediated neurotoxic effect. Conclusion Our observations suggest that Cu(II) enhances the effect of A[beta] on microglial activation and the subsequent neurotoxicity. The Cu(II)-A[beta]-triggered microglial activation involves NF-κB activation and mitochondrial ROS production. Keywords: Cu(II)-A[beta] complex, Aggregation, Microglia, Reactive oxygen species, Tumor necrosis factor-[alpha], Nitric oxide, NF-кB