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E22G Pathogenic Mutation of β-Amyloid (Aβ) Enhances Misfolding of Aβ40 by Unexpected Prion-like Cross Talk between Aβ42 and Aβ40
- Yoo, Brian K., Xiao, Yiling, McElheny, Dan, Ishii, Yoshitaka
- Journal of the American Chemical Society 2018 v.140 no.8 pp. 2781-2784
- Alzheimer disease, amyloid, carbon, fluorescence, heterozygosity, mutation, neurodegenerative diseases, prion diseases, prions, stable isotopes
- Cross-seeding of misfolded amyloid proteins is postulated to induce cross-species infection of prion diseases. In sporadic Alzheimer’s disease (AD), misfolding of 42-residue β-amyloid (Aβ) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded Aβ mimics prions, interactions of misfolded 42-residue Aβ42 with more abundant 40-residue Aβ40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic (“Arctic”) mutation of Aβ40 can enhance misfolding of Aβ via cross-seeding from wild-type (WT) Aβ42 fibril. Thioflavin T (ThT) fluorescence analysis suggested that misfolding of E22G Aβ40 was enhanced by adding 5% (w/w) WT Aβ42 fibril as “seed”, whereas WT Aβ40 was unaffected by Aβ42 fibril seed. ¹³C SSNMR analysis revealed that such cross-seeding prompted formation of E22G Aβ40 fibril that structurally mimics the seed Aβ42 fibril, suggesting unexpected cross talk of Aβ isoforms that potentially promotes early onset of AD. The SSNMR approach is likely applicable to elucidate structural details of heterogeneous amyloid fibrils produced in cross-seeding for amyloids linked to neurodegenerative diseases.