Identification of key regions and residues controlling Aß folding and assembly.

ABSTRACT

Amyloid ß-protein (Aß) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different Aß40 and Aß42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology. Our experiments revealed that the assembly of Aß42 was more sensitive to chiral substitutions than was Aß40 assembly. Substitutions at identical positions in the two peptides often, but not always, produced the same effects on assembly. Sites causing substantial effects in both Aß40 and Aß42 include His14, Gln15, Ala30, Ile31, Met35, and Val36. Sites whose effects were unique to Aß40 include Lys16, Leu17, and Asn 27, whereas sites unique to Aß42 include Phe20 and Ala21. These sites may be appropriate targets for therapeutic agents that inhibit or potentiate, respectively, these effects.