E22G Pathogenic Mutation of beta-Amyloid (A beta) Enhances Misfolding of A beta 40 by Unexpected Prion-like Cross Talk between A beta 42 and A beta 40

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 beta-amyloid (A beta) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded A beta mimics prions, interactions of misfolded 42-residue A beta 42 with more abundant 40-residue A beta 40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic (Arctic) mutation of A beta 40 can enhance misfolding of A beta via cross-seeding from wild-type (WT) A beta 42 fibril. Thioflavin T (ThT) fluorescence analysis suggested that misfolding of E22G A beta 40 was enhanced by adding 5% (w/w) WT A beta 42 fibril as seed, whereas WT A beta 40 was unaffected by A beta 42 fibril seed. C-13 SSNMR analysis revealed that such cross-seeding prompted formation of E22G A beta 40 fibril that structurally mimics the seed A beta 42 fibril, suggesting unexpected cross talk of A beta 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.