Abstract
Amyloid β-protein (Aβ) 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 Aβ40 and Aβ42 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 Aβ42 was more sensitive to chiral substitutions than was Aβ40 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 Aβ40 and Aβ42 include His14, Gln15, Ala30, Ile31, Met35, and Val36. Sites whose effects were unique to Aβ40 include Lys16, Leu17, and Asn 27, whereas sites unique to Aβ42 include Phe20 and Ala21. These sites may be appropriate targets for therapeutic agents that inhibit or potentiate, respectively, these effects.
Highlights
Alzheimer’s disease (AD) is the most common cause of late-life dementia[1] and recently has been identified as the 6th leading cause of death in the U.S.2
This allowed us to determine the effects of specific amino acids on peptide oligomerization, secondary structure, fibril assembly, and fibril morphology and if any differences in effects were observed between Aβ40 and Aβ42
Determination of amyloid β-protein structure-assembly relationships is essential for knowledge-based design of therapeutic agents
Summary
Alzheimer’s disease (AD) is the most common cause of late-life dementia[1] and recently has been identified as the 6th leading cause of death in the U.S.2. By definition, the substituted amino acids differ from the wild type amino acids in polarity, charge, hydrophobicity, or size of the amino acid side-chains These differences per se may be responsible for any changes, or lack of changes, in peptide folding and assembly, as opposed to the differences indicating how the wild type amino is involved these processes. To avoid these interpretive difficulties, we employed a scanning D-amino acid substitution strategy. This allowed us to determine the effects of specific amino acids on peptide oligomerization, secondary structure, fibril assembly, and fibril morphology and if any differences in effects were observed between Aβ40 and Aβ42
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