Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance
- 1Department of Chemistry, Yale University, New Haven, Connecticut, USA
- 2San Diego Institute of Science, Altos Labs, San Diego, California, USA
Abstract
ApoE lipidation determines Aβ interaction and clearanceInherited variations in the apolipoprotein E (APOE) gene are the largest genetic determinant for late-onset Alzheimer’s disease, with the APOEε4 allele conferring the highest risk. Although APOE was shown to modulate amyloid beta (Aβ) pathology in a genotype-specific manner (APOEε4>APOEε3>APOEε2), it remains an open question whether these differences are due directly to isoform-specific interactions between ApoE and Aβ or indirect effects on Aβ clearance. To disentangle how single ApoE mutations confer vastly different effects on Aβ pathology, we investigated how both the ApoE isoform and lipidation modulate its binding to Aβ species, and its effect on Aβ uptake and cytotoxicity in human astrocytes. We found that ApoE lipidation, not isoform, has the biggest impact on its interaction with Aβ, on the uptake of Aβ by astrocytes, and on Aβ-induced cytotoxicity. Specifically, unlipidated ApoE preferentially interacts with Aβ oligomers and fibrils, which substantially inhibits their uptake by astrocytes. Conversely, lipidated ApoE showed no interaction with Aβ oligomers and had a reduced ability to inhibit Aβ uptake. Our observations suggest that previously reported ApoE isoform-specific differences in Aβ oligomer levels are not driven by intrinsic sequence-specific differences in the affinity between ApoE and Aβ, but potentially by isoform-specific differences in ApoE lipidation in the brain. We propose that the impaired lipidation of ApoE4 in the brain increases levels of unlipidated ApoE, which then bind toxic Aβ oligomers and reduce their clearance by astrocytes. Such a mechanism underscores the therapeutic potential of interventions aimed at increasing ApoE lipidation.
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BibTeX
@article{nurmakova2026apolipoprotein,
title = {{Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance}},
author = {Kamila Nurmakova and Gregory-Neal W. Gomes and Zachary A. Levine},
journal = {The Journal of biological chemistry},
year = {2026},
month = aug,
doi = {10.1016/j.jbc.2026.113494},
url = {https://europepmc.org/article/PMC/PMC13722068},
note = {CC BY},
}
RIS
TY - JOUR
TI - Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance
AU - Kamila Nurmakova
AU - Gregory-Neal W. Gomes
AU - Zachary A. Levine
PY - 2026
DA - 2026/08/27
JO - The Journal of biological chemistry
DO - 10.1016/j.jbc.2026.113494
UR - https://europepmc.org/article/PMC/PMC13722068
AB - ApoE lipidation determines Aβ interaction and clearanceInherited variations in the apolipoprotein E (APOE) gene are the largest genetic determinant for late-onset Alzheimer’s disease, with the APOEε4 allele conferring the highest risk. Although APOE was shown to modulate amyloid beta (Aβ) pathology in a genotype-specific manner (APOEε4>APOEε3>APOEε2), it remains an open question whether these differences are due directly to isoform-specific interactions between ApoE and Aβ or indirect effects on Aβ clearance. To disentangle how single ApoE mutations confer vastly different effects on Aβ pathology, we investigated how both the ApoE isoform and lipidation modulate its binding to Aβ species, and its effect on Aβ uptake and cytotoxicity in human astrocytes. We found that ApoE lipidation, not isoform, has the biggest impact on its interaction with Aβ, on the uptake of Aβ by astrocytes, and on Aβ-induced cytotoxicity. Specifically, unlipidated ApoE preferentially interacts with Aβ oligomers and fibrils, which substantially inhibits their uptake by astrocytes. Conversely, lipidated ApoE showed no interaction with Aβ oligomers and had a reduced ability to inhibit Aβ uptake. Our observations suggest that previously reported ApoE isoform-specific differences in Aβ oligomer levels are not driven by intrinsic sequence-specific differences in the affinity between ApoE and Aβ, but potentially by isoform-specific differences in ApoE lipidation in the brain. We propose that the impaired lipidation of ApoE4 in the brain increases levels of unlipidated ApoE, which then bind toxic Aβ oligomers and reduce their clearance by astrocytes. Such a mechanism underscores the therapeutic potential of interventions aimed at increasing ApoE lipidation.
SN - 0021-9258
SN - 1083-351X
ER -