Proteomic analysis of hippocampus in mice following long-term exposure to low levels of copper.

Recent studies suggest that copper exposure, even at very low levels, can produce significant toxic effects on the brains of mice. This study is aimed to explore the effects of low levels of copper on the hippocampal proteome of mice. Two-dimensional fluorescence difference gel electrophoresis was performed on hippocampal homogenate obtained from mice, which were given either drinking water only (control) or water supplemented with 0.13 ppm copper (copper-treated) for a period of 8 months beginning at an age of 3 months. A total of 9 differentially expressed proteins between copper-treated mice and control mice were identified. Protein functional analysis revealed that the altered proteins mainly involved energy metabolism-related proteins, synaptic proteins, molecular chaperones and cellular structural components. Among these differentially expressed proteins, serine racemase (SRR) and glial fibrillary acidic protein (GFAP) were significantly down-regulated and up-regulated, respectively, in the hippocampus of copper-treated mice compared with the control mice. SRR was shown to be involved in memory formation. The increased expression of GFAP, an astrocyte marker, indicated that long-term low levels of copper exposure caused activation of the inflammatory response, a process linked to spatial memory impairment. In agreement with the data from proteomic analysis, memory impairment was observed in copper-treated mice as measured by the Morris water maze test. In summary, this study has identified a number of abnormally expressed proteins in the hippocampus of copper-treated mice, and the identified protein, such as SRR, together with inflammatory responses, as evidenced by the increased expression of GFAP, could contribute to memory impairment resulting from copper exposure. Our findings provide insights for a better understanding of copper neurotoxicity at the protein level in response to low levels of copper exposure.