Cited by 23Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNanoparticle-Based Drug Delivery

Protective ApoE variants support neuronal function by effluxing oxidized phospholipids

Open access
Ralhan, Isha, Do, Alison D., Bae, Ju-Young, Feringa, Femke M., Cai, Wendy, Chang, Jinlan, Chik, Kennedi, Lee, Nathanael Y.J. +5 more·2026·Neuron

Abstract

Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by extracting oxidized unsaturated lipids through the ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids, leading to endolysosomal dysfunction. By reducing the oxidized lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity caused by excitotoxicity. Our findings reveal how ApoE2 and ApoE3Ch help protect neurons from neurodegeneration.

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Crossref · 10.1016/j.neuron.2025.10.040

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  1. Goutagny, 2013, Hippocampal Oscillatory Activity in Alzheimer’s Disease: Toward the Identification of Early Biomarkers?, Aging Dis., 4, 134

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Authors
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y. J., Gerry, C. J., van der Kant, R., Jackson, J., Ricq, E. L., & Ioannou, M. S.
Affiliations
  • University of Alberta (CA)
  • Vrije Universiteit Amsterdam (NL)
Corresponding author
Ioannou, Maria S.
Venue
Neuron
Publisher
Elsevier BV
Published
2026-02
Volume
114
Issue
4
Pages
661-678.e10
ISSN
0896-6273 (ISSN-L)
OpenAlex
W4416918377
Cited by
23
References
62
Citations by year
2026: 23
FWCI
14.80
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
Funders
  • Canada Research Chairs (2021-00027)
  • The Chan Zuckerberg Initiative (DAF2022-250616)
  • ZonMw (WE.03-2019-13, 733050515, 09150172110086)
  • Women and Children's Health Research Institute
  • Canadian Institutes of Health Research (173321, 181551)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
apolipoprotein E, APOE2, APOE ε4, ferroptosis, oxidized phospholipids, lipid efflux, lipoprotein particles, endolysosomal dysfunction, excitotoxicity, neuroprotection, Alzheimer's disease, lipid trafficking, neurons
MeSH terms
Animals, Apolipoproteins E, Cells, Cultured, Humans, Lysosomes, Neurons, Oxidation-Reduction, Phospholipids, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

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