LAUSR

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 (Aβarc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβarc 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 Aβ42arc peptide aggregates into amyloid fibrils significantly faster than wild-type Aβ (Aβ42wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aβ42arc compared to Aβ42wt fibrils. The Aβ42arc peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42wt fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42arc 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 Aβ42arc aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.