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 () and Suman De ()
Additional contact information
Zengjie Xia: University of Cambridge
Emily E. Prescott: University of Sheffield
Agnieszka Urbanek: University of Sheffield
Hollie E. Wareing: University of Sheffield
Marianne C. King: University of Sheffield
Anna Olerinyova: University of Sheffield
Helen Dakin: University of Cambridge
Tom Leah: University of Sheffield
Katy A. Barnes: University of Sheffield
Martyna M. Matuszyk: University of Sheffield
Eleni Dimou: University of Cambridge
Eric Hidari: University of Cambridge
Yu P. Zhang: University of Cambridge
Jeff Y. L. Lam: University of Cambridge
John S. H. Danial: University of Cambridge
Michael R. Strickland: Washington University School of Medicine
Hong Jiang: Washington University School of Medicine
Peter Thornton: AstraZeneca
Damian C. Crowther: AstraZeneca
Sohvi Ohtonen: University of Eastern Finland
Mireia Gómez-Budia: University of Eastern Finland
Simon M. Bell: University of Sheffield
Laura Ferraiuolo: University of Sheffield
Heather Mortiboys: University of Sheffield
Adrian Higginbottom: University of Sheffield
Stephen B. Wharton: University of Sheffield
David M. Holtzman: Washington University School of Medicine
Tarja Malm: University of Eastern Finland
Rohan T. Ranasinghe: University of Cambridge
David Klenerman: University of Cambridge
Suman De: University of Sheffield

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-49028-z

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