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Cited by 67Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease

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Xia, Zengjie, Prescott, Emily E., Urbanek, Agnieszka, Wareing, Hollie E., King, Marianne C., Olerinyova, Anna, Dakin, Helen, Leah, Tom +23 more·2024·Nature Communications
DOI 10.1038/s41467-024-49028-zPMC PMC11144216

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Abstract

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

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Authors
Xia, Z., Prescott, E. E., Urbanek, A., Wareing, H. E., King, M. C., Olerinyova, A., Dakin, H., Leah, T., Barnes, K. A., Matuszyk, M. M., Dimou, E., Hidari, E., Zhang, Y. P., Lam, J. Y. L., Danial, J. S. H., Strickland, M. R., Jiang, H., Thornton, P., Crowther, D. C., Ohtonen, S., Gómez-Budia, M., Bell, S. M., Ferraiuolo, L., Mortiboys, H., Higginbottom, A., Wharton, S. B., Holtzman, D. M., Malm, T., Ranasinghe, R. T., Klenerman, D., & De, S.
Affiliations
  • University of Cambridge (GB)
  • University of Sheffield (GB)
  • University of St Andrews (GB)
  • Washington University in St. Louis (US)
  • AstraZeneca (United Kingdom) (GB)
  • University of Eastern Finland (FI)
Corresponding author
  • Ranasinghe, Rohan T.
  • Klenerman, David
  • De, Suman
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-01
Volume
15
Issue
1
Pages
4695-4695
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-49028-z
PMC
PMC11144216
OpenAlex
W4399256436
Cited by
67
References
20
Citations by year
2026: 29 · 2025: 31 · 2024: 7
FWCI
17.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
Funders
  • AstraZeneca
  • Cure Alzheimer's Fund
  • UK Research and Innovation (MR/V023861/1)
  • Dementia Research UK
  • Alzheimer's Society
  • Good Ventures Foundation
  • National Institute for Health and Care Research
  • Royal Society
  • Parkinson's UK (F1301)
  • Academy of Medical Sciences (SBF006∖1038, SGL028\1097)
  • UK Dementia Research Institute
  • National Institutes of Health (NS090934, AG047644)
  • Medical Research Council (MR/V023861/1)
  • Engineering and Physical Sciences Research Council (2594676)
  • National Institute on Aging (R01AG047644, RF1AG047644)
  • National Institute of Neurological Disorders and Stroke (R01NS090934, RF1NS090934)
  • H2020 European Research Council (669237)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, amyloid-beta, Alzheimer's disease, APOE ε4, co-aggregation, amyloid fibril formation, APOE isoforms, amyloid-beta clearance, glial cells, neuroinflammation, membrane damage, single-molecule imaging
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Female, Humans, Male, Mice, Transgenic, Neuroglia, Amyloid beta-Peptides, Protein Isoforms, Mice, Apolipoprotein E4, Protein Aggregation, Pathological, Protein Aggregates

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