Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease

Chongyang Chen, Xin Jiang, Yingchao Li, Haitao Yu, Shupeng Li, Zaijun Zhang, Hua Xu, Ying Yang, Gongping Liu, Feiqi Zhu, Xiaohu Ren, Liangyu Zou, Benhong Xu, Jianjun Liu, Peter Spencer, Xifei Yang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)144-156
Number of pages13
JournalFree Radical Biology and Medicine
Volume135
DOIs
StatePublished - May 1 2019

Fingerprint

Copper
Alzheimer Disease
Phosphorylation
Phosphoproteins
Organelle Biogenesis
Mitochondrial Dynamics
Glycogen Synthase Kinase 3
Phosphopeptides
Long-Term Potentiation
Calcineurin
Mitogen-Activated Protein Kinase 1
Electron Transport Complex IV
Threonine
Mitogen-Activated Protein Kinases
Drinking Water
Proteomics
Serine
Hydrogen Peroxide
Energy Metabolism
Chlorides

Keywords

  • Axonal degeneration
  • Low-dose copper exposure
  • Mitochondria
  • Phosphoproteomics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease. / Chen, Chongyang; Jiang, Xin; Li, Yingchao; Yu, Haitao; Li, Shupeng; Zhang, Zaijun; Xu, Hua; Yang, Ying; Liu, Gongping; Zhu, Feiqi; Ren, Xiaohu; Zou, Liangyu; Xu, Benhong; Liu, Jianjun; Spencer, Peter; Yang, Xifei.

In: Free Radical Biology and Medicine, Vol. 135, 01.05.2019, p. 144-156.

Research output: Contribution to journalArticle

Chen, Chongyang ; Jiang, Xin ; Li, Yingchao ; Yu, Haitao ; Li, Shupeng ; Zhang, Zaijun ; Xu, Hua ; Yang, Ying ; Liu, Gongping ; Zhu, Feiqi ; Ren, Xiaohu ; Zou, Liangyu ; Xu, Benhong ; Liu, Jianjun ; Spencer, Peter ; Yang, Xifei. / Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease. In: Free Radical Biology and Medicine. 2019 ; Vol. 135. pp. 144-156.
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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

AU - Yang, Xifei

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.

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KW - Mitochondria

KW - Phosphoproteomics

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