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<p>The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer’s disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and <i>APP</i><sup><i>NL-G-F</i></sup> mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.</p>

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Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer’s disease mouse models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Timothy J. Trinklein,
  • Stanislav S. Rubakhin,
  • Samuel Okyem,
  • Seth W. Croslow,
  • Marisa Asadian,
  • K. R. Sabitha,
  • Orly Lazarov,
  • Fan Lam,
  • Jonathan V. Sweedler

摘要

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer’s disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APPNL-G-F mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.