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APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
Open accessAbstract
APOE4 -disrupted intracellular lipid homeostasis in human and yeast cells was reversed by promoting phospholipid synthesis through choline supplementation.
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In the citing paper
“the effects of APOE on the composition of LDs themselves remains unexplored”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Sienski et al., 2021
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Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE ε4 is known to disrupt lipid homeostasis and immune response and to cause mitochondrial dysfunction [31–34]”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Blocking fatty acid desaturation through inhibition of stearoyl-CoA desaturase 1, an enzyme elevated in Alzheimer's disease patient brains, or supplementing cells with choline reduced LD accumulation in APOE4 iPSCs (Astarita et al., 2011; Sienski et al., 2021).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Sienski et al., 2021
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This finding aligns with studies showing benefits of dietary choline intake and supplementation on cognitive performance in human individuals and in animal models71–78.”
From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [78]
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In the citing paper
“Examining two isogenic pairs, Sienski et al. showed that APOE4 astrocytes were choline deficient, causing increased unsaturated fatty acids and lipid droplet accumulation in which choline supplementation restored the cellular lipidome to its basal state.”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Sienski et al., 2021
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ACAT activity and LD levels increase with age [64–66], AD, and APOE4 [67, 68], suggesting low levels of FC that will limit apoE lipidation and its downstream effects.”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [67]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Astrocytes expressing ApoE4 typically have more lipid droplets compared to those expressing ApoE2 or ApoE3 [49][50][51][52][53] .”
From ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction (2026) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A consensus has emerged that APOE4 represents a hypomorphic variant that is less effective in detoxifying and feeding the neurons.”
From Isoform- and cell-state-specific lipidation of ApoE in astrocytes (2022) · cites this paper as Sienski et al., 2021
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Recent in vitro studies discovered that APOE4 promotes the accumulation of unsaturated triglycerides and lipid droplets in iPSC-derived astrocytes10”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“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 [12]
The cited source says what the claim attributes to it.
In the citing paper
“Live cell microscopy of iMG with a fluorescent dye for neutral lipids (LipidSpot) showed greater LD accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG, similar to recent reports in isogenic iMG4 and astrocytes20.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [20]
The cited source says what the claim attributes to it.
In the citing paper
“ApoE4 disrupts intracellular lipid homeostais [50]”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [50]
The cited source says what the claim attributes to it.
In the citing paper
“E4 expressing astrocytes (Windham et al., 2024; Farmer et al., 2019; Sienski et al., 2021) and E4 microglia (Machlovi et al., 2022; Victor et al., 2022; Haney et al., 2024) both accumulate more lipid droplets than neutral AD-risk ε3/ε3 (E3) expressing cells.”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Sienski et al., 2021
The cited source says what the claim attributes to it.
In the citing paper
“Previous work has identified that the APOE genotype correlates with changes in fatty acid saturation in whole cell lipidomics measurements16,24,30.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
The cited source says what the claim attributes to it.
In the citing paper
“Astrocytic lipid droplets also accumulate in an APOE genotype-dependent manner.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
The cited source says what the claim attributes to it.
In the citing paper
“studies in various model systems have linked APOE4 with increased astrocytic lipid droplets15,16,20,24.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
The cited source says what the claim attributes to it.
In the citing paper
“APOE4 astrocytes accumulate unsaturated triglycerides in lipid droplets in both mouse15,16 and human iPSC-derived astrocytes24,30.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
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In the citing paper
“Our well-powered hiPSC study identified common and divergent pathways when compared to earlier APOE4 hiPSC studies (Lin et al., 2018; Sienski et al., 2021; Wang et al., 2018).”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Sienski et al., 2021
The cited source says what the claim attributes to it.
In the citing paper
“Another report found that APOE4 expressed in iPSC-derived astrocytes led to increased accumulation of unsaturated fatty acids and lipid droplet formation (17).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [17]
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Metadata
- Authors
- Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., Milo, B., Graziosi, A., Baru, V., Lewis, C. A., Kellis, M., Sabatini, D. M., Tsai, L.-H., & Lindquist, S.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- National Institutes of Health (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Duke University (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sienski, Grzegorz
- Narayan, Priyanka
- Bonner, Julia Maeve
- Tsai, Li-Huei
- Lindquist, Susan
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2021-03-03
- Volume
- 13
- Issue
- 583
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC8218593
- OpenAlex
- W3135225782
- Cited by
- 336
- References
- 97
- Citations by year
- 2026: 59 · 2025: 80 · 2024: 72 · 2023: 65 · 2022: 42 · 2021: 18
- FWCI
- 30.90
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-01-21)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- Howard Hughes Medical Institute
- National Institute of Mental Health
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of Neurological Disorders and Stroke (ALTF 829-2015, NIH/NIA K99, AG055697-03, R01 CA103866, RF1 AG048029, RF1 AG062377, U01 NS110453, R01 AG062335, R01 AG058002)
- NIH Office of the Director (AG055697-03)
- National Cancer Institute, Cairo University
- National Institute of Development Administration
- Neurodegeneration Consortium
- NIH Clinical Center (R01 CA103866)
- Damon Runyon Cancer Research Foundation
- European Molecular Biology Organization (ALTF 829-2015)
- Helen Hay Whitney Foundation
- Alzheimer’s Association (AARF-19-616816)
- NIH Blueprint for Neuroscience Research (R01 AG062335, R01 AG058002, RF1 AG048029, RF1 AG062377)
- Robert A. and Renee E. Belfer Family Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- APOE ε4, glial cells, induced pluripotent stem cells, phospholipid synthesis, choline supplementation, Alzheimer's disease, lipid metabolism
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Homeostasis, Humans, Neuroglia, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells
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