The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Aβ fibril formation without increasing protofibril formation

A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid beta-protein precursor or presenilins. Whereas some amyloid beta-protein precursor mutations alter its metabolism through effects on A beta production, the pathogenic effects of those that alter amino acid residues within the A beta sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-A beta mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect A beta production, synthetic A beta(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using A beta(140)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R A beta were markedly inhibited despite enhanced fibril formation. These N-terminal A beta mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of A beta peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.