A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-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 Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.
N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly
