The Arctic mutation accelerates Aβ aggregation in SDS through reducing the helical propensity of residues 15–25

Abstract

Mutations within the β-amyloid peptide (Aβ) sequence that cause early onset familial Alzheimer’s disease (FAD) have been shown to promote Aβ aggregation. How these FAD-related mutants increase the aggregative ability of Aβ is not fully understood. Here, we characterized the effect of the Arctic variant (E22G) on the conformational stability of Aβ using various forms of spectroscopy and kinetic analyses, including nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy and transmission electron microscopy (TEM). The E22G mutation in the Arctic variant reduced the α-helical propensity and conformational stability of Aβ on residues 15–25. This mutation also caused an increase in both α-helix-to-β-strand conversion and fibril nucleation rates. Our results suggest that the α-helical propensity of residues 15–25 may play a determinant role in the aggregative ability of Aβ. This may provide a structural basis for understanding the molecular mechanism of Aβ aggregation.

• β-Amyloid peptide
• CD
• discordant helix
• familial Alzheimer’s disease
• NMR

Declaration of interest

The authors report no conflicts of interest.This work was supported by the National Sciences Council of the Republic of China (NSC 96-2311-B-010-010-MY3; to T. H. Lin), the Taipei Veterans General Hospital, Taiwan, Republic of China (V100C-180; to T. H. Lin), a grant from Ministry of Education, Aiming for the Top University Plan, and an internal grant from MacKay Medical College (1011B05; to Y. C. Chen). The NMR spectra were obtained at the High-Field Biomacromolecular NMR Core Facility, which was supported by the National Research Program for Genomic Medicine and Instrumentation Center at the National Taiwan University.

Supplementary material available online

Supplemental Figure S1.