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

Author

Listed:
  • Zengjie Xia

    (University of Cambridge
    UK Dementia Research Institute at 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
    UK Dementia Research Institute at University of Cambridge
    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
    UK Dementia Research Institute at University of Cambridge)

  • Eric Hidari

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge)

  • Yu P. Zhang

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge)

  • Jeff Y. L. Lam

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge)

  • John S. H. Danial

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge
    University of St Andrews, North Haugh)

  • Michael R. Strickland

    (Washington University School of Medicine
    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
    University of Sheffield)

  • Laura Ferraiuolo

    (University of Sheffield)

  • Heather Mortiboys

    (University of Sheffield
    University of Sheffield
    University of Sheffield, Western Bank)

  • Adrian Higginbottom

    (University of Sheffield
    University of Sheffield)

  • Stephen B. Wharton

    (University of Sheffield
    University of Sheffield)

  • David M. Holtzman

    (Washington University School of Medicine)

  • Tarja Malm

    (University of Eastern Finland)

  • Rohan T. Ranasinghe

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge)

  • David Klenerman

    (University of Cambridge
    UK Dementia Research Institute at University of Cambridge)

  • Suman De

    (University of Sheffield
    University of Sheffield
    University of Sheffield, Western Bank)

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.

Suggested Citation

  • 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, 2024. "Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49028-z
    DOI: 10.1038/s41467-024-49028-z
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    References listed on IDEAS

    as
    1. Ankur Jain & Ruijie Liu & Biswarathan Ramani & Edwin Arauz & Yuji Ishitsuka & Kaushik Ragunathan & Jeehae Park & Jie Chen & Yang K. Xiang & Taekjip Ha, 2011. "Probing cellular protein complexes using single-molecule pull-down," Nature, Nature, vol. 473(7348), pages 484-488, May.
    2. Se Hoon Choi & Young Hye Kim & Matthias Hebisch & Christopher Sliwinski & Seungkyu Lee & Carla D’Avanzo & Hechao Chen & Basavaraj Hooli & Caroline Asselin & Julien Muffat & Justin B. Klee & Can Zhang , 2014. "A three-dimensional human neural cell culture model of Alzheimer’s disease," Nature, Nature, vol. 515(7526), pages 274-278, November.
    3. Suman De & David C. Wirthensohn & Patrick Flagmeier & Craig Hughes & Francesco A. Aprile & Francesco S. Ruggeri & Daniel R. Whiten & Derya Emin & Zengjie Xia & Juan A. Varela & Pietro Sormanni & Franz, 2019. "Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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