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

Abstract

Amyloid-β peptide (Aβ) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in Aβ are associated with early onset familial AD, and the Arctic mutant E22G (Aβ^arc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβ^arc by mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the wild-type Aβ, against which Bri2 BRICHOS has a major effect on both secondary nucleation and fibril end elongation. The monomeric Aβ42^arc peptide aggregates into amyloid fibrils significantly faster than wild-type Aβ (Aβ42^wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aβ42^arc compared to Aβ42^wt fibrils. The Aβ42^arc peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42^wt fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42^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 Aβ42^arc aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.