Designing peptide inhibitors for oligomerization and toxicity of Alzheimer's β-amyloid peptide

Convergent biochemical and genetic evidence suggests that the formation of beta-amyloid (A beta) deposits in the brain is an important and, probably, seminal step in the development of Alzheimer's disease (AD). Recent studies support the hypothesis that A beta soluble oligomers are the pathogenic species that prompt the disease. Inhibiting A beta self-oligomerization could, therefore, provide a novel approach to treating the underlying cause of AD. Here, we designed potential peptide-based aggregation inhibitors containing A beta amino acid sequences (KLVFF) from part of the binding region responsible for A beta self-association (residues 16-20), with RG-/-GR residues added at their N- and C-terminal ends to aid solubility. Two such peptides (RGKLVFFGR, named OR1, and RGKLVFFGR-NH2, named OR2) were effective inhibitors of A beta fibril formation, but only one of these peptides (OR2) inhibited A beta oligomer formation. Interestingly, this same OR2 peptide was the only effective inhibitor of A beta toxicity toward human neuroblastoma SH-SY5Y cells. Our data support the idea that A beta oligomers are responsible for the cytotoxic effects of A beta and identify a potential peptide inhibitor for further development as a novel therapy for AD.