APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics
10 affiliations
- 1Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- 2Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
- 3Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
- 4Alzheimer Center Amsterdam, Department of Neurology, Amsterdam University Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands
- 5Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
- 6DataTecnica, Washington, DC, USA
- 7Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- 8Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
- 9Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. [email protected]
- 10Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected]
Abstract
Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.
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BibTeX
@article{cunilopez2026apoe,
title = {{APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics}},
author = {Carla Cuní‐López and Jessica T. Root and Ying Hao and Niek Blomberg and Sascha Koppes-den Hertog and Dylan C. Sacks and Amber E. Trujillo and Rodolfo Ghirlando and Isabelle Kowal and Jacob Epstein and Linda G. Yang and Mark Cookson and Elise Marsan and Rik van der Kant and Martin A. Giera and Yue Andy Qi and Priyanka S. Narayan},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76565-6},
url = {https://doi.org/10.1038/s41467-026-76565-6},
note = {CC BY},
}
RIS
TY - JOUR
TI - APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics
AU - Carla Cuní‐López
AU - Jessica T. Root
AU - Ying Hao
AU - Niek Blomberg
AU - Sascha Koppes-den Hertog
AU - Dylan C. Sacks
AU - Amber E. Trujillo
AU - Rodolfo Ghirlando
AU - Isabelle Kowal
AU - Jacob Epstein
AU - Linda G. Yang
AU - Mark Cookson
AU - Elise Marsan
AU - Rik van der Kant
AU - Martin A. Giera
AU - Yue Andy Qi
AU - Priyanka S. Narayan
PY - 2026
DA - 2026/08/19
JO - Nature Communications
DO - 10.1038/s41467-026-76565-6
UR - https://doi.org/10.1038/s41467-026-76565-6
AB - Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.
SN - 2041-1723
ER -