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

ABSTRACT

Amyloid-ß peptide (Aß) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in Aß are associated with early onset familial AD, and the Arctic mutant E22G (Aßarc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aßarc by mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the wild-type Aß, against which Bri2 BRICHOS has a major effect on both secondary nucleation and fibril end elongation. The monomeric Aß42arc peptide aggregates into amyloid fibrils significantly faster than wild-type Aß (Aß42wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aß42arc compared to Aß42wt fibrils. The Aß42arc peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aß42wt fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aß42arc 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 Aß42arc aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.