Isoform- and cell-state-specific lipidation of ApoE in astrocytes
Open accessAbstract
Apolipoprotein E transports lipids and couples metabolism between astrocytes and neurons. The E4 variant (APOE4) affects these functions and represents a genetic predisposition for Alzheimer's disease, but the molecular mechanisms remain elusive. We show that ApoE produces different types of lipoproteins via distinct lipidation pathways. ApoE forms high-density lipoprotein (HDL)-like, cholesterol-rich particles via the ATP-binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress-associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol-rich lipoproteins, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10-20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. We propose that fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion.
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Lipid droplets (LDs) have important roles in ageing and Alzheimer's disease (AD).
“Moreover, LDs—cellular organelles containing lipids such as glycerolipids and cholesterol—were recently found to have important roles in ageing and Alzheimer's disease (AD)10–15.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [11]
The Discussion links lipid-droplet accumulation in astrocytes to aging and describes a possible connection to late-onset AD. But the Limitations of the study says its proposed effects on brain aging and AD remain speculative, so this source does not establish that lipid droplets have important roles in both. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased lipid droplet accumulation in ApoE4-expressing astrocytes has been thought to result from dysregulation of lipid homeostasis in neuroinflammation.
“Increased LD accumulation in ApoE4-expressing astrocytes has been thought to result from the dysregulation of lipid homeostasis in neuroinflammation (20)(21)(22).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [22]
The Introduction and Discussion report that ApoE4-expressing astrocytes accumulate more lipid droplets than ApoE3 astrocytes and describe altered lipid handling. They do not attribute that accumulation to dysregulated lipid homeostasis in neuroinflammation; the Discussion instead discusses aging, stress, and metabolic perturbation. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNo major isoform differences could be observed in promoting efflux for BODIPY-cholesterol loaded CCF-STTG1.
“Under these conditions, no major isoform differences could be observed (Figure 8D), in agreement with previously reported data.49”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [49]
Functional diversity of APOE isoforms profoundly impacts astrocyte biology.
“The functional diversity of APOE isoforms profoundly impacts astrocyte biology.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [4]
The HEK293 expression system does not fully recapitulate the lipidation state or post-translational modifications of ApoE in primary astrocytes or neurons.
“Third, the HEK293 expression system does not fully recapitulate the lipidation state or post-translational modifications of ApoE in primary astrocytes or neurons”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [47]
The Discussion and the section on mechanisms of ApoE lipidation describe cell-dependent lipidation in astrocytic and other cell systems. Our copy does not compare HEK293-expressed ApoE with ApoE from primary astrocytes or neurons, or address the claimed difference in post-translational modifications (searched: HEK293 and post-translational modifications). (LLM, conf=0.76)
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Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
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 · see citing works
Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473 · see citing works
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 · see citing works
Abnormal in vivo metabolism of apolipoprotein E4 in humans.
Gregg, R. E., Zech, L. A., Schaefer, E. J., Stark, D., Wilson, D., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112645 · Cited by 345 · see citing works
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
<i>APOE4</i> 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 · see citing works
Weisgraber, K. H. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42621-5 · Cited by 304 · see citing works
Gong, J.-S., Kobayashi, M., Hayashi, H., Zou, K., Sawamura, N., Fujita, S. C., Yanagisawa, K., & Michikawa, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203934200 · Cited by 214 · see citing works
Westerlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164 · see citing works
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 · see citing works
de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 2
- Chen, J., Li, Q., and Wang, J. (2011). Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc. Natl. Acad. Sci. U S A 108, 14813-14818.
- Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., and Pericak-Vance, M.A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923.
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Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
Kozlova, A., Zhang, S., Sudwarts, A., Zhang, H., Smirnou, S., Byeon, S. K., Thapa, C., Sun, X., Stephenson, K., Zhao, X., et al. (2025) · Nature · doi:10.1038/s41586-025-09486-x · Cited by 53 · see citing works
Zhao, J., Ikezu, T. C., Lu, W., Macyczko, J. R., Li, Y., Lewis-Tuffin, L. J., Martens, Y. A., Ren, Y., Zhu, Y., Asmann, Y. W., et al. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03444-y · Cited by 25 · see citing works
Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
Tian, X., Rivera, E. K., Hwang, I., Nikitina, A. A., Smith, J. A., Cho, Y. J., Sala‐Jarque, J., DuBose, A., Andriola, C., Gollan‐Myers, T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70589 · Cited by 7 · see citing works
Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
Hernandez Arriaza, R., Reil, D., Fatuzzo, N., Fu, M., Dai, Y., Fernandez Martinez, D., Jiang, H., Holtzman, D. M., Greicius, M. D., & Khosla, C. (2025) · Biochemistry · doi:10.1021/acs.biochem.5c00503 · Cited by 2 · see citing works
- Authors
- Lindner, K., Beckenbauer, K., van Ek, L. C., Titeca, K., de Leeuw, S. M., Awwad, K., Hanke, F., Korepanova, A. V., Rybin, V., van der Kam, E. L., Mohler, E. G., Tackenberg, C., Lakics, V., & Gavin, A.-C.
- Affiliations
- University of Geneva (CH)
- AbbVie (Germany) (DE)
- European Molecular Biology Laboratory (DE)
- AbbVie (United States) (US)
- University of Zurich (CH)
- Corresponding author
- Gavin, Anne-Claude
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 38
- Issue
- 9
- Pages
- 110435
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4214591900
- Cited by
- 84
- References
- 13
- Citations by year
- 2026: 11 · 2025: 25 · 2024: 13 · 2023: 25 · 2022: 10
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by-nc-nd)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, APOE ε4, astrocytes, lipid modification, lipoprotein assembly, ABCA1, high-density lipoprotein, triglyceride-rich lipoproteins, cholesterol-rich lipoproteins, Alzheimer's disease
- MeSH terms
- Apolipoproteins E, Astrocytes, Triglycerides, Protein Isoforms, Apolipoprotein E4
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