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.

Amyloid inhibition by molecular chaperones in vitro can be translated to Alzheimer's pathology in vivo

“…Further, the reductions of Aβ42 oligomer generation from in vitro experiments are shown. 1,9 (C) The impact of BRICHOS on Aβ42-associated neurotoxicity was measured as reduction of γ-oscillations in mouse hippocampal slices. 1,14 This journal is © The Royal Society of Chemistry 20xx…”

Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue

“…S8j). Also, the microscopic mechanisms of rh Bri2 BRICHOS D148N species against Aβ42 fibrillization are similar to the wildtype species, 36,51 both the secondary nucleation and elongation of Aβ42 are affected (ESI† Fig. S8a–i).…”

A “grappling hook” interaction balances self-assembly and chaperone activity of Nucleophosmin 1

“…Aβ 42 was produced as described previously 43 . Aggregation kinetics were monitored in solution by measuring total ThT fluorescence using a POLARstar Omega microplate reader (BMG Labtech, Germany) with an excitation filter at 440 nm and an emission filter at 480 nm.…”