Nature Communications (Jun 2024)
Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
- Zengjie Xia,
- Emily E. Prescott,
- Agnieszka Urbanek,
- Hollie E. Wareing,
- Marianne C. King,
- Anna Olerinyova,
- Helen Dakin,
- Tom Leah,
- Katy A. Barnes,
- Martyna M. Matuszyk,
- Eleni Dimou,
- Eric Hidari,
- Yu P. Zhang,
- Jeff Y. L. Lam,
- John S. H. Danial,
- Michael R. Strickland,
- Hong Jiang,
- Peter Thornton,
- Damian C. Crowther,
- Sohvi Ohtonen,
- Mireia Gómez-Budia,
- Simon M. Bell,
- Laura Ferraiuolo,
- Heather Mortiboys,
- Adrian Higginbottom,
- Stephen B. Wharton,
- David M. Holtzman,
- Tarja Malm,
- Rohan T. Ranasinghe,
- David Klenerman,
- Suman De
Affiliations
- Zengjie Xia
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Emily E. Prescott
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Agnieszka Urbanek
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Hollie E. Wareing
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Marianne C. King
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Anna Olerinyova
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Helen Dakin
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Tom Leah
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Katy A. Barnes
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Martyna M. Matuszyk
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Eleni Dimou
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Eric Hidari
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Yu P. Zhang
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Jeff Y. L. Lam
- Yusuf Hamied Department of Chemistry, University of Cambridge
- John S. H. Danial
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Michael R. Strickland
- Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine
- Hong Jiang
- Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine
- Peter Thornton
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca
- Damian C. Crowther
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca
- Sohvi Ohtonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
- Mireia Gómez-Budia
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
- Simon M. Bell
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Laura Ferraiuolo
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Heather Mortiboys
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Adrian Higginbottom
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- Stephen B. Wharton
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- David M. Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine
- Tarja Malm
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
- Rohan T. Ranasinghe
- Yusuf Hamied Department of Chemistry, University of Cambridge
- David Klenerman
- Yusuf Hamied Department of Chemistry, University of Cambridge
- Suman De
- Sheffield Institute for Translational Neuroscience, Division of Neurosciences, University of Sheffield
- DOI
- https://doi.org/10.1038/s41467-024-49028-z
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 18
Abstract
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.
