Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain

Amyloid-beta peptide (A beta) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in A beta are associated with early onset familial AD, and the Arctic mutant E22G (A beta(arc)) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of A beta(arc) by mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the wild-type A beta, against which Bri2 BRICHOS has a major effect on both secondary nudeation and fibril end elongation. The monomeric A beta 42(arc) peptide aggregates into amyloid fibrils significantly faster than wild-type A beta (A beta 42(wt)), as monitored by thiollavin T (ThT) binding, but the final ThT intensity was strikingly lower for A beta 42(arc) compared to A beta 42(wt) fibrils. The A beta 42(arc) peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while A beta 42(wt) fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the A beta 42(arc) fibril surface and interferes with the macroscopic fibril arrangement by promoting single-filament fibril formation. This study provides mechanistic insights on how BRICHOS efficiently affects the aggressive A beta 42(arc) aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.

Automated summary

This study demonstrates that the Bri2 BRICHOS protein efficiently inhibits the aggregation of the highly aggregation-prone variant A beta(arc), resulting in delayed fibril formation. The protein interferes with A beta aggregation by affecting secondary nucleation and fibril end elongation.