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Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer’s disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics

Author

Listed:
  • Shuling Xu

    (University of Wisconsin-Madison)

  • Zhijun Zhu

    (University of Wisconsin-Madison)

  • Daniel G. Delafield

    (University of Wisconsin-Madison)

  • Michael J. Rigby

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Gaoyuan Lu

    (University of Wisconsin-Madison)

  • Megan Braun

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Luigi Puglielli

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    Veterans Affairs Medical Center)

  • Lingjun Li

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin- Madison)

Abstract

Dysregulated glycerophospholipid (GP) metabolism in the brain is associated with the progression of neurodegenerative diseases including Alzheimer’s disease (AD). Routine liquid chromatography-mass spectrometry (LC-MS)-based large-scale lipidomic methods often fail to elucidate subtle yet important structural features such as sn-position, hindering the precise interrogation of GP molecules. Leveraging high-resolution demultiplexing (HRdm) ion mobility spectrometry (IMS), we develop a four-dimensional (4D) lipidomic strategy to resolve GP sn-position isomers. We further construct a comprehensive experimental 4D GP database of 498 GPs identified from the mouse brain and an in-depth extended 4D library of 2500 GPs predicted by machine learning, enabling automated profiling of GPs with detailed acyl chain sn-position assignment. Analyzing three mouse brain regions (hippocampus, cerebellum, and cortex), we successfully identify a total of 592 GPs including 130 pairs of sn-position isomers. Further temporal GPs analysis in the three functional brain regions illustrates their metabolic alterations in AD progression.

Suggested Citation

  • Shuling Xu & Zhijun Zhu & Daniel G. Delafield & Michael J. Rigby & Gaoyuan Lu & Megan Braun & Luigi Puglielli & Lingjun Li, 2024. "Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer’s disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50299-9
    DOI: 10.1038/s41467-024-50299-9
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