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Cited by 55Neuroinflammation and Neurodegeneration MechanismsLipid metabolism and biosynthesisAlzheimer's disease research and treatments

Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4

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Stephenson, Roxan A., Sepulveda, Jordy, Johnson, Kory R., Lita, Adrian, Gopalakrishnan, Jaanam, Acri, Dominic J., Beilina, Alexandra, Cheng, Linling +10 more·2025·Cell Reports
DOI 10.1016/j.celrep.2025.115961PMC PMC12410147

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Abstract

Abstract Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer’s disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer’s disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4- associated disease.

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Authors
Stephenson, R. A., Sepulveda, J., Johnson, K. R., Lita, A., Gopalakrishnan, J., Acri, D. J., Beilina, A., Cheng, L., Yang, L. G., Root, J. T., Ward, M. E., Combs, C., Skarnes, W. C., Cookson, M. R., Shih, H.-Y., Larion, M., Rebeck, G. W., & Narayan, P. S.
Affiliations
  • National Institutes of Health (US)
  • Georgetown University (US)
  • The Jackson Laboratory for Genomic Medicine (US)
Corresponding author
Narayan, Priyanka S.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2025-07
Volume
44
Issue
7
Pages
115961
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2025.115961
PMC
PMC12410147
OpenAlex
W4412372209
Cited by
55
References
23
Citations by year
2026: 39 · 2025: 14 · 2024: 2
FWCI
17.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • The Chan Zuckerberg Initiative
  • National Institute of Diabetes and Digestive and Kidney Diseases (1ZIADK075158)
  • University of California, San Francisco (AG10788, AG09173)
  • National Institute on Aging
  • National Institute of Neurological Disorders and Stroke (R01 NS100704, F99/K00 NS134164)
  • National Cancer Institute
  • National Heart, Lung, and Blood Institute
  • National Eye Institute
  • Massachusetts Institute of Technology
  • National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
triglyceride metabolism, microglia, APOE ε4, lipid droplets, triglyceride synthesis, triglyceride catabolism, microglial activation, inflammation, Alzheimer's disease, induced pluripotent stem cell-derived microglia, lipopolysaccharide, inflammatory cytokines, chemokines, phagocytosis, microglial surveillance, humanized transgenic mice

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