Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Aβ production

Structure. 2014 Mar 4;22(3):387-96. doi: 10.1016/j.str.2013.12.012. Epub 2014 Jan 23.


Proteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimer's disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases α-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases Aβ peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • CHO Cells
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cholesterol / metabolism
  • Cricetulus
  • Humans
  • Lipid Bilayers
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Mutation*
  • Protein Conformation
  • Protein Multimerization
  • Spectroscopy, Fourier Transform Infrared


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Lipid Bilayers
  • Cholesterol