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

Shuling Xu, Zhijun Zhu, Daniel G. Delafield, Michael J. Rigby, Gaoyuan Lu, Megan Braun, Luigi Puglielli and Lingjun Li ()
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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
Gaoyuan Lu: University of Wisconsin-Madison
Megan Braun: University of Wisconsin-Madison
Luigi Puglielli: University of Wisconsin-Madison
Lingjun Li: University of Wisconsin-Madison

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50299-9

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