Trace amounts of copper exacerbate beta amyloid-induced neurotoxicity in the cholesterol-fed mice through TNF-mediated inflammatory pathway.
Evidence has been gathered to suggest that trace amounts of copper induce neurotoxicity by interaction with elevated cholesterol in diet. Step-through task and Morris water maze task were used to evaluate cognitive function in the animals. Although a 16-week copper treatment alone in mice showed no significant change in learning and memory performances, cholesterol treatment significantly induced learning and memory impairments, which could be exacerbated by the co-treatment with copper. Immunohistochemical studies revealed that trace amounts of copper further stimulated the amyloid precursor protein (APP) upregulation and contributed to amyloid beta-peptide (Abeta) deposition in the brain of cholesterol-fed mice. Western blot analysis showed that copper also increased the protein expression levels of tumor necrosis factor-alpha (TNF-alpha) and the degradation of IkappaB proteins in the brain of cholesterol-fed mice. Furthermore, increased production of high inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expressions were detected in the hippocampus and cerebral cortex of copper and cholesterol co-treated mice by immunohistochemical analysis. These findings suggest that trace amounts of copper could induce APP upregulation, activate inflammatory pathway and exacerbate neurotoxicity in cholesterol-fed mice.
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou, Jiangsu Province 221116, PR China.
Jun
J
Lu
Dong-mei
DM
Wu
Yuan-lin
YL
Zheng
Dong-xu
DX
Sun
Bin
B
Hu
Qun
Q
Shan
Zi-feng
ZF
Zhang
Shao-hua
SH
Fan
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D002784:Cholesterol / Q000008:administration & dosage / Q000494:pharmacology*; D003300:Copper / Q000008:administration & dosage / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology; D007859:Learning Disabilities / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D014409:Tumor Necrosis Factor-alpha; D044844:beta-Transducin Repeat-Containing Proteins; D003300:Copper; D002784:Cholesterol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2