Identification of the Key Molecules Involved in Chronic Copper Exposure-Aggravated Memory Impairment in Transgenic Mice of Alzheimer's Disease Using Proteomic Analysis

Article type: Research Article

Authors: Yu, Jun^{a; b; 1} | Luo, Xiaobin^{e; f; 1} | Xu, Hua^{a; *} | Ma, Quan^b | Yuan, Jianhui^b | Li, Xuling^{b; g} | Chang, Raymond Chuen-Chung^c | Qu, Zhongsen^d | Huang, Xinfeng^b | Zhuang, Zhixiong^b | Liu, Jianjun^b | Yang, Xifei^{b; *}

Affiliations: [a] College of Pharmacy, Jinan University, Guangdong, China | [b] Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Guangdong Province, Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China | [c] Laboratory of Neurodegenerative Diseases, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China | [d] Department of Neurology, Shanghai Jiaotong University Affiliated the Sixth Hospital, Shanghai, China | [e] Shen Zhen Kai-Tuo Biotech, Shenzhen, China | [f] Guang Zhou Kai-Tuo Biotech, Guangzhou, China | [g] College of Life Sciences, Shenzhen University, Shenzhen, China

Correspondence: [*] Correspondence to: Dr. Xifei Yang, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen 518055, China. Tel.: +86 75525601914; Fax: +86 75525508584; E-mail: xifeiyang@gmail.com and Dr. Hua Xu, College of Pharmacy, Jinan University, Guangzhou 510632, China. Tel./Fax: +86 20 85220850; E-mail: huax_mail@126.com.

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD.

Keywords: Alzheimer's disease, copper, memory impairment, two-dimensional fluorescence difference gel electrophoresis

DOI: 10.3233/JAD-141776

Journal: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 455-469, 2015