E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer’s
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.
Authors
- Tatsuya Matsunaga
- Mohammad Jafar Tehrani (ORCID: https://orcid.org/0000-0002-7405-2458)
- Mikako Shirouzu (ORCID: https://orcid.org/0000-0002-7997-2149)
- Yu Kodama (ORCID: https://orcid.org/0000-0003-3972-9176)
- Naohiro Kobayashi (ORCID: https://orcid.org/0000-0001-5136-2077)
- Isamu Matsuda (ORCID: https://orcid.org/0000-0002-3032-8934)
- Yoshitaka Ishii (ORCID: https://orcid.org/0000-0002-7724-6469)
- Dan McElheny
- Atsushi Yamagata (ORCID: https://orcid.org/0000-0001-9285-1256)
- Mayuko Sato (ORCID: https://orcid.org/0000-0002-9876-5612)
- Kiminori Toyooka (ORCID: https://orcid.org/0000-0002-6414-5191)
Institutions
- Tokyo Institute of Technology (JP)
- University of Illinois Chicago (US)
- RIKEN Center for Sustainable Resource Science (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1038/s41467-024-51294-w
- Citations
- 11
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 3.59
Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- RIKEN
- National Institute of General Medical Sciences
- RIKEN Center for Biosystems Dynamics Research
- JST-Mirai Program