Abstract
Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Low-dose copper increased the spatial memory impairment of these animals, increased accumulation of intracellular amyloid 1–42 (Aβ1–42), decreased ATP content, increased the positive staining of 8-hydroxyguanosine (8-OHdG), a marker of DNA oxidative damage, and caused apoptosis and a decrease in synaptic proteins. Mitochondrial proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) revealed modulation of 24 hippocampal mitochondrial proteins (14 increased and 10 decreased) in copper-treated vs. untreated 3xTg-AD mice. Nuclear proteomic analysis revealed 43 modulated hippocampal nuclear proteins (25 increased and 18 decreased) in copper-treated 3xTg-AD vs. untreated mice. Classification of modulated mitochondrial and nuclear proteins included functional categories such as energy metabolism, synaptic-related proteins, DNA damage and apoptosis-related proteins, and oxidative stress-related proteins. Among these differentially expressed mitochondrial and nuclear proteins, nine proteins were abnormally expressed in both hippocampus mitochondria and nuclei, including electron transport chain-related proteins NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUAA), cytochrome b-c1 complex subunit Rieske (UCRI), cytochrome c oxidase subunit 5B (COX5B), and ATP synthase subunit d (ATP5H), glycolytic-related pyruvate kinase PKM (KPYM) and pyruvate dehydrogenase E1 component subunit alpha (ODPA). Furthermore, we found coenzyme Q10 (CoQ10), an endogenous mitochondrial protective factor/antioxidant, modulated the expression of 12 differentially expressed hippocampal proteins (4 increased and 8 decreased), which could be classified in functional categories such as glycolysis and synaptic-related proteins, oxidative stress-related proteins, implying that CoQ10 improved synaptic function, suppress oxidative stress, and regulate glycolysis. For the proteomics study, we validated the expression of several proteins related to synapses, DNA and apoptosis. The data confirmed that synapsin-2, a synaptic-related protein, was significantly decreased in both mitochondria and nuclei of copper-exposed 3xTg-AD mice. In mitochondria, dynamin-1 (DYN1), an apoptosis-related proteins, was significantly decreased. In the cellular nuclei, paraspeckle protein 1 (PSPC1) and purin-rich element-binding protein alpha (Purα), two DNA damage-related proteins, were significantly decreased and increased, respectively. We conclude that low-dose copper exposure exacerbates the spatial memory impairment of 3xTg-AD mice and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome. Exposure to copper might therefore contribute to the evolution of AD.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (81673134), Guangdong Provincial Natural Science Foundation (2014A030313715, 2016A030313051), Guangdong Provincial Scheme of Science and Technology (To X.F.Y), Shenzhen Special Fund Project on Strategic Emerging Industry Development (JCYJ20160428143433768, JCYJ20150529164656093, JCYJ20150529153646078, JCYJ20140416122811964, JCYJ20160422143433757) and Sanming Project of Medicine in Shenzhen.
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Supplementary Fig 1. A representative 2D-DIGE gel image of hippocampal mitochondrial proteins from the non-exposed 3xTg-AD mice and copper-exposed 3xTg-AD mice. Hippocampal mitochondrial proteins from the non-exposed 3xTg-AD mice and copper-exposed 3xTg-AD mice were labeled with Cy3 or Cy5 dye, respectively (n=6 for each group). An internal standard protein sample (a mixture of all mitochondria samples) was labeled with the Cy2 dye. The CyDye-labeled samples were combined, and the proteins were co-separated in the first dimension via IEF in 24 cm pH 3–11 nonlinear IPG strips, followed by separation in the second dimension via SDS-PAGE. Spots of interest were manually excised, digested and subjected to identification by MALDI-TOF-MS/MS. (A) Cy2-labeled proteins as internal standards. (B) Cy3-labeled hippocampal mitochondrial proteins of copper-exposed 3xTg-AD mice. (C) Cy5-labeled hippocampal mitochondrial proteins of non-exposed 3xTg-AD mice. (D) The merged image showing Cy2-, Cy3- and Cy5-labeled proteins. (E) Greyscale 2D-DIGE gel image showing 24 differentially expressed protein spots identified by MALDI-TOF-MS/MS (black numbers with white square) in the hippocampal mitochondria of copper-exposed 3xTg-AD mice compared with non-exposed 3xTg-AD mice. Supplementary Fig 2. A representative 2D-DIGE gel image of hippocampal nuclear proteins from the non-exposed 3xTg-AD mice and copper-exposed 3xTg-AD mice. Hippocampal nuclear proteins from the non-exposed 3xTg-AD mice and copper-exposed 3xTg-AD mice were labeled with Cy3 or Cy5 dye, respectively (n=6 for each group). An internal standard protein sample (a mixture of all nucleus samples) was labeled with the Cy2 dye. The CyDye-labeled samples were combined, and the proteins were co-separated in the first dimension via IEF in 24 cm pH 3–11 nonlinear IPG strips, followed by separation in the second dimension via SDS-PAGE. Spots of interest were manually excised, digested and subjected to identification by MALDI-TOF-MS/MS. (A) Cy2-labeled proteins as internal standards. (B) Cy3-labeled hippocampal nuclear proteins of copper-exposed 3xTg-AD mice. (C) Cy5-labeled hippocampal nuclear proteins of non-exposed 3xTg-AD mice. (D) The merged image showing Cy2-, Cy3- and Cy5-labeled proteins. (E) Greyscale 2D-DIGE gel image showing 43 differentially expressed protein spots identified by MALDI-TOF-MS/MS (black numbers with white square) in the hippocampal nucleus of copper-exposed 3xTg-AD mice compared with non-exposed 3xTg-AD mice. Supplementary Fig 3. A representative 2D-DIGE gel image of hippocampal proteins from non-treated 3xTg-AD mice and CoQ10-treated 3xTg-AD mice. Hippocampal proteins from non-treated 3xTg-AD mice and CoQ10-treated 3xTg-AD mice were labeled with Cy3 or Cy5 dye, respectively (n=6 for each group). An internal standard protein sample (a mixture of all hippocampus samples) was labeled with the Cy2 dye. The CyDye-labeled samples were combined, and the proteins were co-separated in the first dimension via IEF in 24 cm pH 3–11 nonlinear IPG strips, followed by separation in the second dimension via SDS-PAGE. Spots of interest were manually excised, digested and subjected to identification by MALDI-TOF-MS/MS. (A) Cy2-labeled proteins as internal standards. (B) Cy3-labeled hippocampus proteins of non-treated 3xTg-AD mice. (C) Cy5-labeled hippocampus proteins of CoQ10-treated 3xTg-AD mice. (D) The merged image showing Cy2-, Cy3- and Cy5-labeled proteins. (E) Greyscale 2D-DIGE gel image showing 12 differentially expressed protein spots identified by MALDI-TOF-MS/MS (black numbers with white square) in the hippocampus of CoQ10-treated 3xTg-AD mice compared with non-treated 3xTg-AD mice. Supplementary Fig 4. Identification of synapsin-2 (A) The MALDI-TOF-MS map of mitochondrial synapsin-2; (B) The amino acid sequences of mitochondrial synapsin-2 in which matched peptide sequence was in red; (C) The MALDI-TOF-MS map of nuclear synapsin-2; (D) The amino acid sequences of nuclear synapsin-2 in which matched peptide sequence was in red. Supplementary Fig 5. Identification of Pura and PSPC1 in nuclei (A) The MALDI-TOF-MS map of Pura; (B) The amino acid sequences of Pura in which matched peptide sequence was in red. (C) The MALDI-TOF-MS map of PSPC1; (D) The amino acid sequences of PSPC1 in which matched peptide sequence was in red. Supplementary Fig 6. Identification of DYN1 in mitochondria (A) The MALDI-TOF-MS map of DYN1; (B) The amino acid sequences of DYN1 in which matched peptide sequence was in red (DOCX 2373 KB)
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Yu, H., Wang, D., Zou, L. et al. Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer’s disease. Arch Toxicol 92, 1363–1382 (2018). https://doi.org/10.1007/s00204-018-2163-6
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DOI: https://doi.org/10.1007/s00204-018-2163-6