Skip to main content
Open Access Publications from the University of California

Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

  • Author(s): Grant, MA
  • Lazo, ND
  • Lomakin, A
  • Condron, MM
  • Arai, H
  • Yamin, G
  • Rigby, AC
  • Teplow, DB
  • et al.

Published Web Location
No data is associated with this publication.

Amyloid β-protein (Aβ) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied Aβ monomer folding and identified a decapeptide segment of Aβ,21Ala-22Glu-23Asp-24Val-25Gly-26Ser-27Asn-28Lys-29Gly-30Ala, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by long-range electrostatic interactions between Lys-28 and either Glu-22 or Asp-23. We hypothesized that turn destabilization might explain the effects of amino acid substitutions at Glu-22 and Asp-23 that cause familial forms of AD and cerebral amyloid angiopathy. To test this hypothesis, limited proteolysis, mass spectrometry, and solution-state NMR spectroscopy were used here to determine and compare the structure and stability of the Aβ(21-30) turn within wild-type Aβ and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies (ΔΔGf) among the mutant peptides. We observed that all of the disease-associated amino acid substitutions at Glu-22 or Asp-23 destabilized the turn and that the magnitude of the destabilization correlated with oligomerization propensity. The Ala21Gly (Flemish) substitution, outside the turn proper (Glu-22-Lys-28), displayed a stability similar to that of the wild-type peptide. The implications of these findings for understanding Aβ monomer folding and disease causation are discussed. © 2007 by The National Academy of Sciences of the USA.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content