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Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

Author

Listed:
  • Zhi Huang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Gennifer E. Merrihew

    (University of Washington)

  • Eric B. Larson

    (University of Washington)

  • Jea Park

    (University of Washington)

  • Deanna Plubell

    (University of Washington)

  • Edward J. Fox

    (Stanford University School of Medicine)

  • Kathleen S. Montine

    (Stanford University School of Medicine)

  • Caitlin S. Latimer

    (University of Washington)

  • C. Dirk Keene

    (University of Washington)

  • James Y. Zou

    (Stanford University School of Medicine)

  • Michael J. MacCoss

    (University of Washington)

  • Thomas J. Montine

    (Stanford University School of Medicine)

Abstract

Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

Suggested Citation

  • Zhi Huang & Gennifer E. Merrihew & Eric B. Larson & Jea Park & Deanna Plubell & Edward J. Fox & Kathleen S. Montine & Caitlin S. Latimer & C. Dirk Keene & James Y. Zou & Michael J. MacCoss & Thomas J., 2023. "Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38376-x
    DOI: 10.1038/s41467-023-38376-x
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    References listed on IDEAS

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    1. Brian C. Searle & Lindsay K. Pino & Jarrett D. Egertson & Ying S. Ting & Robert T. Lawrence & Brendan X. MacLean & Judit Villén & Michael J. MacCoss, 2018. "Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Nicholas F. Fitz & Kyong Nyon Nam & Cody M. Wolfe & Florent Letronne & Brittany E. Playso & Bistra E. Iordanova & Takashi D. Y. Kozai & Richard J. Biedrzycki & Valerian E. Kagan & Yulia Y. Tyurina & X, 2021. "Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
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