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E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer’s

Author

Listed:
  • Mohammad Jafar Tehrani

    (Tokyo Institute of Technology)

  • Isamu Matsuda

    (Tokyo Institute of Technology)

  • Atsushi Yamagata

    (RIKEN Center for Biosystems Dynamics Research)

  • Yu Kodama

    (Tokyo Institute of Technology)

  • Tatsuya Matsunaga

    (Tokyo Institute of Technology
    RIKEN Center for Biosystems Dynamics Research)

  • Mayuko Sato

    (RIKEN Center for Sustainable Resource Science)

  • Kiminori Toyooka

    (RIKEN Center for Sustainable Resource Science)

  • Dan McElheny

    (University of Illinois at Chicago)

  • Naohiro Kobayashi

    (RIKEN Center for Biosystems Dynamics Research)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research)

  • Yoshitaka Ishii

    (Tokyo Institute of Technology
    RIKEN Center for Biosystems Dynamics Research)

Abstract

Arctic (E22G) mutation in amyloid-β (Aβ enhances Aβ40 fibril accumulation in Alzheimer’s disease (AD). Unlike sporadic AD, familial AD (FAD) patients with the mutation exhibit more Aβ40 in the plaque core. However, structural details of E22G Aβ40 fibrils remain elusive, hindering therapeutic progress. Here, we determine a distinctive W-shaped parallel β-sheet structure through co-analysis by cryo-electron microscopy (cryoEM) and solid-state nuclear magnetic resonance (SSNMR) of in-vitro-prepared E22G Aβ40 fibrils. The E22G Aβ40 fibrils displays typical amyloid features in cotton-wool plaques in the FAD, such as low thioflavin-T fluorescence and a less compact unbundled morphology. Furthermore, kinetic and MD studies reveal previously unidentified in-vitro evidence that E22G Aβ40, rather than Aβ42, may trigger Aβ misfolding in the FAD, and prompt subsequent misfolding of wild-type (WT) Aβ40/Aβ42 via cross-seeding. The results provide insight into how the Arctic mutation promotes AD via Aβ40 accumulation and cross-propagation.

Suggested Citation

  • Mohammad Jafar Tehrani & Isamu Matsuda & Atsushi Yamagata & Yu Kodama & Tatsuya Matsunaga & Mayuko Sato & Kiminori Toyooka & Dan McElheny & Naohiro Kobayashi & Mikako Shirouzu & Yoshitaka Ishii, 2024. "E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer’s," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51294-w
    DOI: 10.1038/s41467-024-51294-w
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    References listed on IDEAS

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    1. Antoine Loquet & Nikolaos G. Sgourakis & Rashmi Gupta & Karin Giller & Dietmar Riedel & Christian Goosmann & Christian Griesinger & Michael Kolbe & David Baker & Stefan Becker & Adam Lange, 2012. "Correction: Corrigendum: Atomic model of the type III secretion system needle," Nature, Nature, vol. 488(7413), pages 684-684, August.
    2. Antoine Loquet & Nikolaos G. Sgourakis & Rashmi Gupta & Karin Giller & Dietmar Riedel & Christian Goosmann & Christian Griesinger & Michael Kolbe & David Baker & Stefan Becker & Adam Lange, 2012. "Atomic model of the type III secretion system needle," Nature, Nature, vol. 486(7402), pages 276-279, June.
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