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TitleE22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 7045, Year 2024
Publish dateAug 15, 2024
AuthorsMohammad Jafar Tehrani / Isamu Matsuda / Atsushi Yamagata / Yu Kodama / Tatsuya Matsunaga / Mayuko Sato / Kiminori Toyooka / Dan McElheny / Naohiro Kobayashi / Mikako Shirouzu / Yoshitaka Ishii /
PubMed AbstractArctic (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 ...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.
External linksNat Commun / PubMed:39147751 / PubMed Central
MethodsEM (helical sym.)
Resolution2.5 Å
Structure data

35972

8j47

EMDB-35972, PDB-8j47:
CryoEM Structure of 40-Residue Arctic (E22G) Beta-Amyloid Fibril Derived by Co-Analysis with Solid-State NMR | E22G Abeta40
Method: EM (helical sym.) / Resolution: 2.5 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / amyloid / Alzheimer's / Familial Alzheimer's

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