Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease
Open accessAbstract
Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D(2), which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D(2), and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis.
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PUFA-CE is strongly upregulated in the brain of amyloid mouse models.
“Since PUFA-CE is strongly upregulated in the brain of amyloid mouse models14”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [14]
The Results report an approximately 11-fold increase in CE-22:6, a polyunsaturated cholesterol ester, in PS1-APP mouse forebrain. But they describe only a trend toward increased CE-22:6 in APP mice, and the Discussion says CE elevation was virtually absent in PS1 mice. Thus, 'strongly upregulated' is supported for the PS1-APP model, not amyloid mouse models generally; the supplied passages give no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLipids are central to AD pathogenesis, as suggested by studies showing cholesterol dysregulation in a range of AD models and patients' brains.
“Together with studies showing cholesterol dysregulation in a range of AD models and patients’ brains, these studies suggest lipids are central to AD pathogenesis14–18.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [14]
Elevated CE levels have been reported in AD brains and AD models.
“Elevated CE levels have been reported in AD brains as well as AD models12,14,15.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [14]
Altered lipid metabolism and extrinsic supplementation with various lipid substrates have a major impact on microglial reprogramming.
“Altered lipid metabolism and extrinsic supplementation with various lipid substrates both have a major impact on microglial reprogramming [60,61,62,63,64].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [60]
The Results and Discussion report altered lipid profiles in Alzheimer disease brain tissue and mouse models, but do not link those changes to microglial reprogramming. Searches for microglia and lipid-substrate supplementation found no passage addressing their claimed effects on microglia. (LLM, conf=0.73)
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- Authors
- Chan, R. B., Oliveira, T. G., Cortes, E. P., Honig, L. S., Duff, K. E., Small, S. A., Wenk, M. R., Shui, G., & Di Paolo, G.
- Affiliations
- Columbia University Irving Medical Center (US)
- National University of Singapore (SG)
- Corresponding author
- Shui, Guanghou
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 287
- Issue
- 4
- Pages
- 2678-2688
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3268426
- OpenAlex
- W2013312860
- Cited by
- 630
- References
- 9
- Citations by year
- 2026: 42 · 2025: 60 · 2024: 59 · 2023: 45 · 2022: 52 · 2021: 54 · 2020: 55 · 2019: 41 · 2018: 32 · 2017: 40 · 2016: 42 · 2015: 37 · 2014: 29 · 2013: 22 · 2012: 20
- FWCI
- 15.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Aging (P50AG008702)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD05547)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- Alzheimer's disease, brain lipidome, diacylglycerol, sphingolipids, GM3 ganglioside, cholesterol esters, lysobisphosphatidic acid, sphingomyelin, endolysosomal dysfunction, phospholipase D2, prefrontal cortex, entorhinal cortex, cerebellum, lipid metabolism
- MeSH terms
- Alzheimer Disease, Animals, Brain Chemistry, Cerebellum, Disease Models, Animal, Humans, Lipids, Mice, Transgenic, Lipid Metabolism, Mice
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