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APOE genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics
Abstract
The lipids and proteins that comprise lipid droplets regulate several cellular functions including lipid storage, stress responses, and inflammation. Glial lipid droplets have been implicated in the pathogenesis and progression of Alzheimer’s disease (AD), yet the mechanisms linking genetic risk to lipid droplet biology remain unclear. Here we examined how APOE , the strongest genetic modulator of late-onset AD, impacts lipid droplet composition and dynamics. We defined the lipid droplet-associated proteome and lipidome in human induced pluripotent stem cell-derived astrocytes harboring the three common APOE genotypes: APOE2 (protective), APOE3 (neutral), and APOE4 (risk). Each APOE variant displays distinct lipid droplet-associated proteins and lipids. These molecular changes yield differences in lipophagy; lipid droplets in APOE2 astrocytes undergo autophagic turnover, whereas those in APOE4 astrocytes are resistant to degradation. These findings suggest that impaired lipid droplet clearance, rather than accumulation, distinguishes APOE4 -associated AD risk, and may present a new metabolic node for modulating risk.
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Lipid droplets in ApoE4 astrocytes are resistant to degradation due to impaired autophagy.
“Lipid droplets in ApoE4 astrocytes are also resistant to 275 degradation due to impaired autophagy 50,54 .”
From ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction (2026) · cites this paper as [54]
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Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125
APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07185-7 · Cited by 536
Endoplasmic reticulum dysfunction in neurological disease
Roussel, B. D., Kruppa, A. J., Miranda, E., Crowther, D. C., Lomas, D. A., & Marciniak, S. J. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70238-7 · Cited by 441
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
TCW, J., Qian, L., Pipalia, N. H., Chao, M. J., Liang, S. A., Shi, Y., Jain, B. R., Bertelsen, S. E., Kapoor, M., Marcora, E., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.017 · Cited by 411
ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R. D., & Yin, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108572 · Cited by 379
APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz4564 · Cited by 336
Self-citationLipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.005 · Cited by 316
Fanning, S., Haque, A., Imberdis, T., Baru, V., Barrasa, M. I., Nuber, S., Termine, D., Ramalingam, N., Ho, G. P. H., Noble, T., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.11.028 · Cited by 285
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Farmer, B., Kluemper, J., & Johnson, L. (2019) · Cells · doi:10.3390/cells8020182 · Cited by 164
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104 · cited 2×
“Given the recent research showing that lipid droplets influence disease-associated processes in AD 12, 13, 15, 18, 19, 23, 26, 33, 34 , we hypothesized that the molecular composition of the lipid droplets in APOE2 astrocytes and APOE4 astrocytes was different and could relate to the alleles’…”
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · cited 1×
“Previous work has linked disruptions to autophagy and lysosomal biology with Alzheimer’s disease 55-57 .”
PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
Narayan, P., Sienski, G., Bonner, J. M., Lin, Y.-T., Seo, J., Baru, V., Haque, A., Milo, B., Akay, L. A., Graziosi, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108224 · Cited by 75
Self-citationAPOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses
Friday, C. M., Stephens, I. O., Smith, C. T., Lee, S., Satish, D., Devanney, N. A., Cohen, S., Morganti, J. M., Gordon, S. M., & Johnson, L. A. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106983 · Cited by 33
Protective ApoE variants support neuronal function by extracting peroxidated lipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y., Gerry, C., van der Kant, R., et al. (2025) · bioRxiv · doi:10.1101/2025.03.05.641722 · Cited by 4
Self-citation
Flagged first, then by citations
Research works printed but not linked: 52
- 10.1038/s41580-018-0085-z · DOI · Paper page
- Welte, M. A . Expanding roles for lipid droplets. in Current biology R470–R481 (Elsevier, 2015). · DOI
- Bersuker, K. , et al. A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes. in Developmental cell 97–112.e117 (2018). · DOI · Paper page
- 10.1126/science.aay8085 · DOI · Paper page
- Casey, C.A. , et al. Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution. Journal of Lipid Research 62, 100049 (2021). · DOI · Paper page
- 10.1194/jlr.M056812 · DOI · Paper page
- 10.1016/j.devcel.2018.09.017 · DOI · Paper page
- 10.1016/j.molcel.2020.01.014 · DOI · Paper page
- Stephenson, R.A. , et al. Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia. in bioRxiv 2024.2004.2011.589145 (2024). · DOI · Paper page
- 10.1016/j.neuron.2023.10.023 · DOI · Paper page
- Farmer, B.C. , Walsh, A.E. , Kluemper, J.C. & Johnson, L.A . Lipid Droplets in Neurodegenerative Disorders. Front Neurosci 14, 742 (2020). · DOI · Paper page
- Moulton, M.J. , et al. Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease-associated genes. Proc Natl Acad Sci U S A 118 (2021). · DOI · Paper page
- Hamilton, L.K. , et al. Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease. in Cell stem cell 397–411 (2015). · DOI · Paper page
- Yang, L.G. , March, Z.M. , Stephenson, R.A. & Narayan, P.S . Apolipoprotein E in lipid metabolism and neurodegenerative disease. in Trends in endocrinology and metabolism: TEM 430–445 (2023). · DOI · Paper page
- 10.1038/s41583-023-00776-9 · DOI · Paper page
- 2016, Generation of induced pluripotent stem cells derived from a 77-year-old healthy woman as control for age related diseases, Stem Cell Res, 17, 550, 10.1016/j.scr.2016.09.019 · DOI · Paper page
- 10.1016/j.stem.2022.11.004 · DOI · Paper page
- Feringa, F.M. , et al. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4. bioRxiv (2024). · DOI
- Ralhan, I. , Chang, C.L. , Lippincott-Schwartz, J. & Ioannou, M.S . Lipid droplets in the nervous system. J Cell Biol 220 (2021). · DOI · Paper page
- 10.1016/j.devcel.2022.01.003 · DOI · Paper page
- 10.1083/jcb.201305142 · DOI
- Liu, Y. , et al. Hydroxysteroid dehydrogenase family proteins on lipid droplets through bacteria, C. elegans, and mammals. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1863, 881–894 (2018). · DOI
- 2013, The CRAPome: a contaminant repository for affinity purification–mass spectrometry data, Nature Methods, 10, 730, 10.1038/nmeth.2557 · DOI · Paper page
- Zhou, Y. , et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. in Nature Communications 1523 (2019). · DOI · Paper page
- Beretta, C. , et al. Astrocytic lipid droplets contain MHCII and may act as cogs in the antigen presentation machinery. J Neuroinflammation 22, 117 (2025). · DOI
- 10.1146/annurev-cellbio-031320-101827 · DOI
- 2019, 17B-hydroxysteroid dehydrogenases as acyl thioester metabolizing enzymes, Mol Cell Endocrinol, 489, 107, 10.1016/j.mce.2018.11.012 · DOI · Paper page
- 10.1016/j.cell.2024.04.041 · DOI · Paper page
- 10.1016/j.bbrc.2014.08.097 · DOI · Paper page
- Dias Araújo, A.R. , et al. Surface tension–driven sorting of human perilipins on lipid droplets. Journal of Cell Biology 223 (2024). · DOI · Paper page
- 2023, Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death, Front Cell Dev Biol, 11, 1104725, 10.3389/fcell.2023.1104725 · DOI · Paper page
- 10.1146/annurev-cellbio-120219-035530 · DOI · Paper page
- 10.1080/15548627.2022.2094606 · DOI
- 10.1016/j.cell.2019.1004.1001 · DOI
- 2025, DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis, Journal of Lipid Research, 66, 100700, 10.1016/j.jlr.2024.100700 · DOI · Paper page
- Lukmantara, I. , et al. PI(3)P and DFCP1 regulate the biogenesis of lipid droplets. Molecular Biology of the Cell 33, ar131 (2022). · DOI · Paper page
- 10.1038/s41574-023-00845-0 · DOI · Paper page
- Guo, H. , et al. Identification of Lipophagy-Related Gene Signature for Diagnosis and Risk Prediction of Alzheimer’s Disease. Biomedicines 13 (2025). · DOI · Paper page
- 10.1038/s41580-024-00757-5 · DOI · Paper page
- Bassal, R. , et al. APOE4 impairs autophagy and Aβ clearance by microglial cells. Inflamm Res 74, 61 (2025). · DOI · Paper page
- 2016, Impaired Autophagy in APOE4 Astrocytes, J Alzheimers Dis, 51, 915, 10.3233/JAD-151101 · DOI · Paper page
- 2025, Loss of lysosomal acid lipase contributes to Alzheimer’s disease pathology and cognitive decline, Alzheimers Dement, 21, e70486, 10.1002/alz.70486 · DOI · Paper page
- 2024, Molecular determinants of lipid droplet subpopulations and their fates, FEBS Letters, 598, 1199, 10.1002/1873-3468.14891 · DOI
- Majchrzak, M. , et al. Perilipin membrane integration determines lipid droplet heterogeneity in differentiating adipocytes. Cell Reports 43, 114093 (2024). · DOI
- 2016, Isolation of Lipid Droplets from Cells by Density Gradient Centrifugation, Current Protocols in Cell Biology, 72, 3.15.11
- 2021, Optimized protocol for the identification of lipid droplet proteomes using proximity labeling proteomics in cultured human cells, STAR Protocols, 2, 100579, 10.1016/j.xpro.2021.100579 · DOI
- 2023, A fully automated FAIMS-DIA mass spectrometry-based proteomic pipeline, Cell Rep Methods, 3, 100593, 10.1016/j.crmeth.2023.100593 · DOI
- Feng, Z. , Fang, P. , Zheng, H. & Zhang, X . DEP2: an upgraded comprehensive analysis toolkit for quantitative proteomics data. Bioinformatics 39 (2023). · DOI · Paper page
- 10.1093/bioinformatics/18.suppl_1.S96 · DOI · Paper page
- 10.1021/acs.analchem.1c02826 · DOI
- Ghorasaini, M. , et al. Congruence and Complementarity of Differential Mobility Spectrometry and NMR Spectroscopy for Plasma Lipidomics. Metabolites 12 (2022). · DOI
- 10.1021/jasms.1c00203 · DOI
Cited by
Sorted by citations
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2
ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction
Ralhan, I., Bae, J.-Y., Lee, N. Y., Cai, W., Chang, J., Jarad, S., Gu, H., Zhang, D., & Ioannou, M. S. (2026) · doi:10.64898/2026.09.01.748585
Metadata
- Authors
- Cuní-López, C., Root, J. T., Hao, Y., Kowal, I., Blomberg, N., Ghirlando, R., Yang, L. G., Koppes-den Hertog, S. J., Cookson, M. R., van der Kant, R., Giera, M., Qi, Y. A., & Narayan, P. S.
- Publisher
- openRxiv
- Published
- 2025-08-20
- PMC
- PMC12393358
- Cited by
- 8
- References
- 16
- Type
- Preprint
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