TY - JOUR
T1 - Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease
AU - Chen, Chongyang
AU - Jiang, Xin
AU - Li, Yingchao
AU - Yu, Haitao
AU - Li, Shupeng
AU - Zhang, Zaijun
AU - Xu, Hua
AU - Yang, Ying
AU - Liu, Gongping
AU - Zhu, Feiqi
AU - Ren, Xiaohu
AU - Zou, Liangyu
AU - Xu, Benhong
AU - Liu, Jianjun
AU - Spencer, Peter S.
AU - Yang, Xifei
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Excessive copper can cause neurotoxicity and contribute to the development of some neurological diseases; however, copper neurotoxicity and the potential mechanisms remain poorly understood. We used proteomics and phosphoproteomics to quantify protein changes in the hippocampus of wild-type and 3xTg-AD mice, both of which were treated at 6 months of age with 2 months of drinking water with or without added copper chloride (0.13 ppm concentration). A total of 3960 unique phosphopeptides (5290 phosphorylation sites) from 1406 phosphoproteins was identified. Differentially expressed phosphoproteins involved neuronal and synaptic function, transcriptional regulation, energy metabolism and mitochondrial function. In addition, low-dose copper treatment of wild-type mice decreased hippocampal mitochondrial copy number, mitochondrial biogenesis and disrupted mitochondrial dynamics; these changes were associated with increased hydrogen peroxide production (H 2 O 2 ), reduced cytochrome oxidase activity and decreased ATP content. In 3xTg-AD mice, identical low-dose oral copper treatment increased axonal degeneration, which was associated with altered phosphorylation of Camk2α at T286 and phosphorylation of mitogen-activated protein kinase (ERK1/2), which involved long-term potentiation (LTP) signaling. Mitochondrial dysfunction was mainly related to changes in phosphorylation levels of glycogen synthase kinase-3 beta (GSK3β) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling. In sum, low-dose oral copper treatment changes the phosphorylation of key hippocampal proteins involved in mitochondrial, synaptic and axonal integrity. These data showing that excess of copper speeds some early events of AD changes observed suggest that excess circulating copper has the potential to perturb brain function of wild-type mice and exacerbate neurodegenerative changes in a mouse model of AD.
AB - Excessive copper can cause neurotoxicity and contribute to the development of some neurological diseases; however, copper neurotoxicity and the potential mechanisms remain poorly understood. We used proteomics and phosphoproteomics to quantify protein changes in the hippocampus of wild-type and 3xTg-AD mice, both of which were treated at 6 months of age with 2 months of drinking water with or without added copper chloride (0.13 ppm concentration). A total of 3960 unique phosphopeptides (5290 phosphorylation sites) from 1406 phosphoproteins was identified. Differentially expressed phosphoproteins involved neuronal and synaptic function, transcriptional regulation, energy metabolism and mitochondrial function. In addition, low-dose copper treatment of wild-type mice decreased hippocampal mitochondrial copy number, mitochondrial biogenesis and disrupted mitochondrial dynamics; these changes were associated with increased hydrogen peroxide production (H 2 O 2 ), reduced cytochrome oxidase activity and decreased ATP content. In 3xTg-AD mice, identical low-dose oral copper treatment increased axonal degeneration, which was associated with altered phosphorylation of Camk2α at T286 and phosphorylation of mitogen-activated protein kinase (ERK1/2), which involved long-term potentiation (LTP) signaling. Mitochondrial dysfunction was mainly related to changes in phosphorylation levels of glycogen synthase kinase-3 beta (GSK3β) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling. In sum, low-dose oral copper treatment changes the phosphorylation of key hippocampal proteins involved in mitochondrial, synaptic and axonal integrity. These data showing that excess of copper speeds some early events of AD changes observed suggest that excess circulating copper has the potential to perturb brain function of wild-type mice and exacerbate neurodegenerative changes in a mouse model of AD.
KW - Axonal degeneration
KW - Low-dose copper exposure
KW - Mitochondria
KW - Phosphoproteomics
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U2 - 10.1016/j.freeradbiomed.2019.03.002
DO - 10.1016/j.freeradbiomed.2019.03.002
M3 - Article
C2 - 30862541
AN - SCOPUS:85062734387
SN - 0891-5849
VL - 135
SP - 144
EP - 156
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -