2. Academic Validation
  3. Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4

Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4

  • Cell Rep. 2025 Jul 22;44(7):115961. doi: 10.1016/j.celrep.2025.115961.
Roxan A Stephenson 1,  Jordy Sepulveda 2,  Kory R Johnson 3,  Adrian Lita 4,  Jaanam Gopalakrishnan 5,  Dominic J Acri 6,  Alexandra Beilina 6,  Linling Cheng 1,  Linda G Yang 1,  Jessica T Root 1,  Michael E Ward 3,  Christian Combs 7,  William C Skarnes 8,  Mark R Cookson 6,  Han-Yu Shih 9,  Mioara Larion 4,  G William Rebeck 10,  Priyanka S Narayan 11
Affiliations

Affiliations

  • 1 Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.
  • 3 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 4 Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5 National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • 6 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • 7 Light Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • 8 The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • 9 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • 10 Department of Neuroscience, Georgetown University, Washington, DC, USA.
  • 11 Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Center for Alzheimer's and Related Dementias (CARD), National Institutes of Health, Bethesda, MD, USA. Electronic address: priyanka.narayan@nih.gov.
PMID: 40644302 DOI: 10.1016/j.celrep.2025.115961
Abstract

Changes to cellular lipids 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 the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.

Keywords

APOE; Alzheimer's; CP: Neuroscience; activation; disease; iPSCs; lipid droplets; lipid metabolism; microglia; motility; neuroinflammation; triglycerides.

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