Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer’s disease progression
Open accessAbstract
INTRODUCTION: Tracking spatial lipidomic changes during Alzheimer's disease (AD) progression is crucial for elucidating the underlying mechanisms of the disease. OBJECTIVES: This study aims to investigate the spatial-temporal lipidomic alterations and their associated metabolic enzyme changes during AD progression. METHODS: The spatial lipidomic changes and corresponding alterations in metabolic enzymes during AD progression in amyloid precursor protein/presenilin-1 (APP/PS1) mice were thoroughly analyzed using an advanced ambient mass spectrometry imaging (MSI) technique, complemented by immunofluorescence (IF) imaging. RESULTS: Distinct lipidomic differences were observed between AD and wild-type (WT) mice in both the hippocampus (HP) and thalamus (TH), with the TH region exhibiting more significant lipid changes than the HP. A total of 88 lipid species with age- and region-specific alterations were identified, primarily within the sphingolipid, glycerolipid, and glycerophospholipid metabolic pathways. These metabolic changes were corroborated by IF imaging, which demonstrated spatial variations in the corresponding enzymes within the lipid metabolic pathways. Notably, a significant downregulation of hexosylceramides (HexCers) in the white matter of aged APP/PS1 mice suggests potential white matter abnormalities linked to AD. Correlation analysis further revealed that reduced HexCers were associated with the inhibited sulfatide-HexCer pathway, potentially driven by diminished ARSA levels, a factor known to be involved in microglial activation and inflammation. Additionally, upregulation of diacylglycerol (DG), observed even during the pre-symptomatic phase of AD, suggests DG as an early diagnostic biomarker. A strong correlation between the spatial changes in the DG-to-phosphatidylcholine (PC) ratio and phospholipase C (PLC) expression indicates that DG upregulation may result from PLC activation, a process known to be induced by amyloid β. CONCLUSIONS: This study provides an expanded spatial, temporal, and chemical perspective on AD mechanisms, offering potential avenues for enhancing early diagnosis and therapeutic strategies.
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Multiple myelin-enriched lipid classes (such as galactosylceramides, sulfatides, and plasmalogens) are increasingly recognized as vulnerable nodes in AD.
“multiple myelin-enriched lipid classes (such as galactosylceramides, sulfatides, and plasmalogens) are increasingly recognized as vulnerable nodes in AD [42, 43].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [43]
The Results report altered sulfatides and galactosylceramides in APP/PS1 mice, and the Discussion links these lipids to myelin. The paper therefore supports vulnerability of those classes in an AD mouse model, but the passages do not identify plasmalogens as another affected class; searches for plasmalogens and ether phosphatidylethanolamine found no such finding. (LLM, conf=0.86)
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Flagged first, then by citations
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Cited by
Sorted by citations
Gutierrez-Kuri, E., Marie Garcia-Rogers, J. L., Perez, J., Smith, S., Kenwood, M. R., Archuleta, K. S., Xiao, Y., Campos, G., Barannikov, S., Wang, H., et al. (2026) · doi:10.64898/2026.07.13.738356
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Aebisher, D., Krzysztofińska, A., Smolak, B., Bernat, P., Czajka, W., Kowal, M., Krasoń, S., Dynarowicz, K., Guz, W., & Bartusik‐Aebisher, D. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27167074
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- Authors
- Li, H., Zhao, Z., Zhu, L., Tan, Y., Zhang, Z., Zhang, Z., Kang, J., Lu, H., Peng, W., & Wu, Q.
- Affiliations
- Central South University (CN)
- University of Minnesota (US)
- Second Xiangya Hospital of Central South University (CN)
- Corresponding author
- Peng, Weijun
- Wu, Qian
- Venue
- Journal of Advanced Research
- Publisher
- Elsevier BV
- Published
- 2026-05
- Volume
- 83
- Pages
- 947-964
- ISSN
- 2090-1224 (ISSN-L)
- 2090-1232
- PMC
- PMC13131509
- OpenAlex
- W4413580778
- Cited by
- 3
- References
- 88
- Citations by year
- 2026: 3
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Advanced Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- China Postdoctoral Science Foundation (2022M711733)
- Hunan Provincial Natural Science Foundation (2024JJ2086, 2022JJ20054)
- Science and Technology Program of Hunan Province (2022RC1220)
- National Natural Science Foundation of China (21804142, 22474156, 82374552, 82104967, 22074159)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- Alzheimer's disease, lipid metabolism, APP/PS1 mice, sphingolipid metabolism, glycerophospholipid metabolism, glycerolipid metabolism, hexosylceramide, diacylglycerol, phosphatidylcholine, phospholipase C, amyloid-beta, white matter abnormalities, hippocampus, thalamus, microglial activation, early diagnostic biomarkers
- MeSH terms
- Lipidomics, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Hippocampus, Male, Mice, Transgenic, Amyloid beta-Protein Precursor, Disease Progression, Lipid Metabolism, Mice, Presenilin-1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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