Role of the 'bend' structure in beta-amyloid fibrillogenesis: Use of peptide congeners as structural models

A hallmark of Alzheimer's Disease pathology is the deposition of beta-amyloid peptide (Abeta1--40) as amyloid fibrils in neuritic plaques. Solid state NMR data led to the development of a model for fibrillar Abeta1--40 (Petkova et al., PNAS 99: 16742--16747, 2002). In this model, Abeta1--40 contains two parallel, in-register beta-sheets connected by a "bend" (D23VGSNKG 29). This bend differs from a beta-hairpin, in that the backbone folds over on itself, allowing side chain interactions. It was hypothesized that the dynamics of the "bend" modulate overall conformational change within the peptide affecting both its aggregation propensity and fibril structure.; Several peptide congeners of Abeta1--40 were chemically synthesized to test this hypothesis. Abeta40-lactam(D23/K28), pre-structured the "bend" as in the fibril model, incorporating a lactam bond between the side chains of residues Asp23 and Lys28, involved in salt bridge formation within the fibril. This structure resulted in a peptide that is highly competent for nucleating fibril growth (Sciarretta et al., Biochemistry 44: 6003--6014,2005). A highly soluble, monomeric congener, 4NMe, incorporating N-methyl amino acids in both the N- and C- terminal beta-sheets was designed to address whether this "bend" in Abeta1--40 exists in solution. Both beta-sheets need to be modified in order to abrogate aggregation; modifying only one beta-sheet is not sufficient. Solution NMR studies provide preliminary evidence that a similar "bend" structure may exist in solution. Various other peptide congeners altered the "bend" structure of Abeta1--40 suggesting that even small changes in the bend region can affect aggregation propensity and fibril structure. Finally, a familial mutation of beta-Amyoid associated with Cerebral Amyloid Angiopathy, located near the "bend" region, "Iowa" D23N, increased the rate of aggregation. Solid state NMR studies demonstrated a novel structure of the fibril with beta-sheets that appear to be out of register by two residues. This may help provide an explanation for the pathological findings associated with this mutation.; In conclusion, the studies presented provide evidence that "bend" structure is important in modulating the folding of Abeta peptides. In addition, the "bend" structure may affect the conformational plasticity of Abeta1--40, allowing different fibril morphologies to exist in the various disease states.