Mitochondrial molecular abnormalities revealed by proteomic analysis of hippocampal organelles of mice triple transgenic for alzheimer disease

Haitao Yu, Xuemei Lin, Dian Wang, Zaijun Zhang, Yi Guo, Xiaohu Ren, Benhong Xu, Jianhui Yuan, Jianjun Liu, Peter Spencer, Jian Zhi Wang, Xifei Yang

Research output: Contribution to journalArticle

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Abstract

Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1–42 (Aβ1–42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55%), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolismrelated proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.

Original languageEnglish (US)
Article number74
JournalFrontiers in Molecular Neuroscience
Volume11
DOIs
StatePublished - Mar 9 2018

Fingerprint

Organelles
Proteomics
Transgenic Mice
Alzheimer Disease
Dynamin I
Two-Dimensional Difference Gel Electrophoresis
Proteins
Mitochondrial Proteins
Electron Transport
Nuclear Proteins
Amyloid
DNA Damage
Adenosine Triphosphate
Biomarkers
Phosphorylation
Apoptosis
Staining and Labeling
Entorhinal Cortex
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Computational Biology

Keywords

  • Alzheimer’s disease (AD)
  • Biomarkers
  • Mitochondrial/nuclear proteomics

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Mitochondrial molecular abnormalities revealed by proteomic analysis of hippocampal organelles of mice triple transgenic for alzheimer disease. / Yu, Haitao; Lin, Xuemei; Wang, Dian; Zhang, Zaijun; Guo, Yi; Ren, Xiaohu; Xu, Benhong; Yuan, Jianhui; Liu, Jianjun; Spencer, Peter; Wang, Jian Zhi; Yang, Xifei.

In: Frontiers in Molecular Neuroscience, Vol. 11, 74, 09.03.2018.

Research output: Contribution to journalArticle

Yu, Haitao ; Lin, Xuemei ; Wang, Dian ; Zhang, Zaijun ; Guo, Yi ; Ren, Xiaohu ; Xu, Benhong ; Yuan, Jianhui ; Liu, Jianjun ; Spencer, Peter ; Wang, Jian Zhi ; Yang, Xifei. / Mitochondrial molecular abnormalities revealed by proteomic analysis of hippocampal organelles of mice triple transgenic for alzheimer disease. In: Frontiers in Molecular Neuroscience. 2018 ; Vol. 11.
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abstract = "Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1–42 (Aβ1–42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55{\%}), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolismrelated proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.",
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AU - Yu, Haitao

AU - Lin, Xuemei

AU - Wang, Dian

AU - Zhang, Zaijun

AU - Guo, Yi

AU - Ren, Xiaohu

AU - Xu, Benhong

AU - Yuan, Jianhui

AU - Liu, Jianjun

AU - Spencer, Peter

AU - Wang, Jian Zhi

AU - Yang, Xifei

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AB - Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1–42 (Aβ1–42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55%), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolismrelated proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.

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