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Title: Amyloid Fibril Formation of Arctic Amyloid-β 1-42 Peptide is Efficiently Inhibited by the BRICHOS Domain.
Author: Zhong X, Kumar R, Wang Y, Biverstål H, Ingeborg Jegerschöld C, J B Koeck P, Johansson J, Abelein A, Chen G.
Journal: ACS Chem Biol; 2022 Aug 19; 17(8):2201-2211. PubMed ID: 35876740.
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.

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