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

• 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 Aβarcby 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 Aβ42arcpeptide 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 Aβ42arccompared to Aβ42wtfibrils. The Aβ42arcpeptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42wtfibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42arcfibril 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 Aβ42arcaggregation, resulting in both delayed fibril formation kinetics and altered fibril structure. 

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Alzheimer

amyloid-β peptide

Arctic

Bri2 BRICHOS

amyloid

amyloid beta protein[1-42]

bri2 protein

chaperone

monomer

oligomer

protein

recombinant protein

thioflavine

unclassified drug

amyloid beta protein

peptide

peptide fragment

peptide I

receptor for activated C kinase

Alzheimer disease

amino acid sequence

Article

brichos domain

fluorescence intensity

gene mutation

kinetics

neurotoxicity

protein aggregation

protein domain

chemistry

human

metabolism

Amyloid beta-Peptides

Humans

Molecular Chaperones

Peptide Fragments

Peptides

Receptors for Activated C Kinase

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)