Protective ApoE variants support neuronal function by extracting peroxidated lipids
Open accessAbstract
SUMMARY: ApoE mediates the transport of lipids from neurons to glial lipid droplets. ApoE4, a major risk factor for Alzheimer’s disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) variants confer resistance to developing the disease, yet little is known regarding how these protective variants affect lipid transport. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health in vitro and in intact rodent hippocampi. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by preferentially extracting peroxidated unsaturated lipids through the neuronal ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids leading to endolysosomal dysfunction. By reducing the peroxidated lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity. Our findings reveal a new mechanism by which ApoE2 and ApoE3Ch isoforms protect neurons from neurodegenerative disease. Highlights: ApoE2 and ApoE3Ch reduce neuronal ferroptosis by peroxidated lipid efflux via ABCA7 Lysosomal defects caused by lipid peroxidation are rescued by ApoE2 and ApoE3Ch ApoE2 and ApoE3Ch particles protect ApoE4 hippocampi from toxicity ApoE2 and ApoE3Ch particles rescue impaired neuronal activity in ApoE4 hippocampi
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Rapid single-step induction of functional neurons from human pluripotent stem cells
Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., Marro, S., Patzke, C., Acuna, C., Covy, J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.029 · Cited by 1,644 · see citing works
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · see citing works
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357 · see citing works
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 · see citing works
Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., & Taylor, J. M. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112130 · Cited by 829 · see citing works
Cataldo, A., Peterhoff, C., Troncoso, J., Gómez-Isla, T., Hyman, B., & Nixon, R. (2000) · American Journal of Pathology · doi:10.1016/s0002-9440(10)64538-5 · Cited by 789 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Arboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0611-3 · Cited by 598 · see citing works
Liu, L., MacKenzie, K. R., Putluri, N., Maletić-Savatić, M., & Bellen, H. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.024 · Cited by 556 · see citing works
Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.211 · Cited by 532 · see citing works
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441 · see citing works
Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains
Karch, C. M., Jeng, A. T., Nowotny, P., Cady, J., Cruchaga, C., & Goate, A. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050976 · Cited by 328 · see citing works
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias
Martens, Y. A., Zhao, N., Liu, C.-C., Kanekiyo, T., Yang, A. J., Goate, A. M., Holtzman, D. M., & Bu, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.004 · Cited by 316 · see citing works
Self-generated theta oscillations in the hippocampus
Goutagny, R., Jackson, J., & Williams, S. (2009) · Nature Neuroscience · doi:10.1038/nn.2440 · Cited by 301 · see citing works
Self-citationApolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.008 · Cited by 298 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30001 · Cited by 222 · see citing works
Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Van Acker, Z. P., Bretou, M., & Annaert, W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0323-7 · Cited by 222 · see citing works
Nuriel, T., Angulo, S. L., Khan, U., Ashok, A., Chen, Q., Figueroa, H. Y., Emrani, S., Liu, L., Herman, M., Barrett, G., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01444-0 · Cited by 181 · see citing works
DeMattos, R. B., Brendza, R. P., Heuser, J. E., Kierson, M., Cirrito, J. R., Fryer, J., Sullivan, P. M., Fagan, A. M., Han, X., & Holtzman, D. M. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00049-3 · Cited by 180 · see citing works
ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Rawat, V., Wang, S., Sima, J., Bar, R., Liraz, O., Gundimeda, U., Parekh, T., Chan, J., Johansson, J. O., Tang, C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1400-19.2019 · Cited by 165 · see citing works
Carlesimo, G. A., Piras, F., Orfei, M. D., Iorio, M., Caltagirone, C., & Spalletta, G. (2015) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2014.12.001 · Cited by 159 · see citing works
A Novel In Vitro Preparation: the Intact Hippocampal Formation
Khalilov, I., Esclapez, M., Medina, I., Aggoun, D., Lamsa, K. P., Leinekugel, X., Khazipov, R., & Ben‐Ari, Y. (1997) · Neuron · doi:10.1016/s0896-6273(00)80956-3 · Cited by 150 · see citing works
The endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140 · see citing works
Cooper, J. M., Lathuiliere, A., Migliorini, M., Arai, A. L., Wani, M. M., Dujardin, S., Muratoglu, S. C., Hyman, B. T., & Strickland, D. K. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100715 · Cited by 122 · see citing works
Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy
Belaidi, A. A., Masaldan, S., Southon, A. G., Kalinowski, P., Acevedo, K. M., Appukuttan, A. T., Portbury, S. D., Lei, P., Agarwal, P., Leurgans, S. E., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01568-w · Cited by 121 · see citing works
Johnson, L. A., Olsen, R. H. J., Merkens, L. S., DeBarber, A. E., Steiner, R. D., Sullivan, P. M., Maeda, N., & Raber, J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.12.016 · Cited by 105 · see citing works
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103 · see citing works
Thomas, S., Ritter, B., Verbich, D., Sanson, C., Bourbonnière, L., McKinney, R. A., & McPherson, P. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809746200 · Cited by 102 · see citing works
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 2× · see citing works
“The protective effects of ApoE2 and ApoE3Ch have been recently linked to reduced receptor binding and lipid uptake in neurons and microglia 16 , but how these protective variants affect lipid efflux from neurons and the type of lipids being transported remains unclear.”
Hubin, E., Verghese, P. B., van Nuland, N., & Broersen, K. (2019) · FEBS Letters · doi:10.1002/1873-3468.13428 · Cited by 73 · see citing works
Driving factors of neuronal ferroptosis
Jacquemyn, J., Ralhan, I., & Ioannou, M. S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.01.010 · Cited by 69 · see citing works
Self-citationEndosomal recycling reconciles the Alzheimer’s disease paradox
Small, S. A., & Petsko, G. A. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abb1717 · Cited by 58 · see citing works
ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism
Kawatani, K., Holm, M., Starling, S. C., Martens, Y. A., Zhao, J., Lü, W., Ren, Y., Li, Z., Jiang, P., Jiang, Y., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02372-w · Cited by 55 · see citing works
Autolysosomal exocytosis of lipids protect neurons from ferroptosis
Ralhan, I., Chang, J., Moulton, M. J., Goodman, L. D., Lee, N. Y. J., Plummer, G., Pasolli, H. A., Matthies, D., Bellen, H. J., & Ioannou, M. S. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202207130 · Cited by 42 · see citing works
Self-citationA Neuron‐Glia Co‐culture System for Studying Intercellular Lipid Transport
Ioannou, M. S., Liu, Z. J., & Lippincott‐Schwartz, J. (2019) · Current Protocols in Cell Biology · doi:10.1002/cpcb.95 · Cited by 36 · see citing works
Self-citationLysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins
Luke, C. J., Markovina, S. T., Good, M. L., Wight, I. E., Thomas, B. J., Linneman, J. M., Lanik, W. E., Koroleva, O., Coffman, M. R., Miedel, M. T., et al. (2022) · Communications Biology · doi:10.1038/s42003-021-02953-x · Cited by 34 · see citing works
Single-Step PCR-Based Genetic Sex Determination of Rat Tissues and Cells
Dhakal, P., & Soares, M. J. (2017) · BioTechniques · doi:10.2144/000114548 · Cited by 33 · see citing works
The ABC's of Alzheimer risk gene ABCA7
Duchateau, L., Wawrzyniak, N., & Sleegers, K. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13805 · Cited by 33 · see citing works
Bossaerts, L., Hens, E., Cacace, R., Asselbergh, B., & Broeckhoven, C. V. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01346-3 · Cited by 21 · see citing works
A lentiviral system for efficient knockdown of proteins in neuronal cultures
Ritter, B., Ferguson, S. M., Camilli, P. V. D., & McPherson, P. S. (2017) · MNI Open Research · doi:10.12688/mniopenres.12766.1 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Triggering ferroptosis in neurodegenerative diseases
Nguyen, T. P. M., Alves, F. M., Lane, D. J. R., Bush, A. I., & Ayton, S. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.06.008 · Cited by 50 · see citing works
Cuní‐López, C., Root, J. T., Hao, Y., Kowal, I., Blomberg, N., Ghirlando, R., Yang, L. G., Hertog, S. K.-D., Cookson, M., van der Kant, R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.19.669163 · Cited by 7 · see citing works
Self-citationDisrupted lipid homeostasis as a pathogenic mechanism in ABCA7 ‐associated Alzheimer's disease risk
Nam, Y., DeRosa, B. A., Ramírez, A. M., Ayele, B. A., Whitehead, P. L., Adams, L. D., Golightly, C. G., Starks, T. D., Laverde-Paz, M. J., Cukier, H. N., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71312
Lee, R. J., Rivas‐Serna, I. M., Theisen, E. K., Bibo, A., Hardy, E. B., Cheng, W., Zhou, Z., Chavez-Rios, J. S., Forward, J. C., Pham, T., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.26.754678
- Authors
- 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., Jackson, J., Ricq, E. L., & Ioannou, M. S.
- Affiliations
- University of Alberta (CA)
- Vrije Universiteit Amsterdam (NL)
- Kisbee Therapeutics, Cambridge, MA, 02139 USA
- Department of Functional Genomics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Corresponding author
- Ioannou, Maria S.
- Venue
- bioRxiv
- Publisher
- openRxiv
- Published
- 2025-03-10
- OpenAlex
- W4408294188
- Semantic Scholar
- 887d782e26a6e15a30d56f3bd9882cd9b4e67988
- Cited by
- 4
- References
- 45
- Citations by year
- 2026: 2 · 2025: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- ZonMw (733050515)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- apolipoprotein E, APOE2, APOE ε4, ferroptosis, lipid peroxidation, ABCA7, lipoprotein particles, endolysosomal dysfunction, hippocampus, Alzheimer's disease, neuroprotection, unsaturated lipids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review