Phosphoproteome analysis of an early onset mouse model (TgCRND8) of Alzheimer's disease reveals temporal changes in neuronal and glia signaling pathways

Authors

  • Fangjun Wang,

    1. Key Lab of Separation Sciences for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, P. R. China
    2. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
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    • These authors contributed equally to this work.

  • Alexandre P. Blanchard,

    1. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
    2. Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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    • These authors contributed equally to this work.

  • Fred Elisma,

    1. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
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  • Matthew Granger,

    1. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
    2. Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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  • Hongbin Xu,

    1. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
    2. Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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  • Steffany A. L. Bennett,

    1. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
    2. Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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  • Daniel Figeys,

    Corresponding author
    • Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
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  • Hanfa Zou

    1. Key Lab of Separation Sciences for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, P. R. China
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  • Colour Online: See the article online to view Figs. , and in colour.

Correspondence: Dr. Daniel Figeys, University of Ottawa – BMI, 451 Smyth Road Ottawa K1H 8M5, Canada

E-mail: dfigeys@uottawa.ca

Fax: 613-562-5655

Abstract

Sustained exposure to soluble amyloid β (Aβ42) oligomers is predicted to impair synaptic function in the hippocampal-entorhinal circuit, signaling synaptic loss and precipitating cognitive impairment in Alzheimer's disease. Regional changes in overall patterns of protein phosphorylation are likely crucial to promote transition from a presymptomatic to a symptomatic state in response to accumulating Aβ42. Here, we used unbiased proteomic approaches to compare the phosphoproteome of presymptomatic and symptomatic TgCRND8 mice and identify network disruptions in signaling pathways implicated in the manifestation of behavioral indices of learning and memory impairment. Phosphopeptide enrichment with triple isotopic dimethylation labeling combined with online multidimensional separation and MS was used to profile phosphoproteome changes in 2- and 6-month-old TgCRND8 mice and congenic littermate controls. We identified 1026 phosphopeptides representing 1168 phosphorylation sites from 476 unique proteins. Of these, 595 phosphopeptides from 293 unique proteins were reliably quantified and 139 phosphopeptides were found to change significantly in the hippocampus of TgCRND8 mice following conversion from a presymptomatic to a symptomatic state.

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