Chemistry

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

Document Type

Article

Abstract

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.

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

10-16-2007

Volume

104

Issue

42

First Page

16522

Last Page

16527

ISSN

0027-8424

DOI

10.1073/pnas.0705197104

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