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

Mohammad Jafar Tehrani, Isamu Matsuda, Atsushi Yamagata, Yu Kodama, Tatsuya Matsunaga, Mayuko Sato, Kiminori Toyooka, Dan McElheny, Naohiro Kobayashi, Mikako Shirouzu and Yoshitaka Ishii ()
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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
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51294-w

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