Recognition sequence design for peptidyl modulators of β-amyloid aggregation and toxicity

beta-Amyloid (A beta), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit A beta toxicity, based on linking a recognition element for A beta to a disrupting element designed to interfere with A beta aggregation. One such compound, with the 15-25 sequence of A beta as the recognition element and a lysine hexamer as the disrupting element, altered A beta aggregation kinetics and protected cells from A beta toxicity [Ghanta et al. (1996) J. Biol. Chem. 271, 29525]. To optimize the recognition element, peptides of 4-8 residues composed of overlapping sequences within the 15-25 domain were synthesized, along with hybrid compounds containing those recognition sequences coupled to a lysine hexamer, None of the recognition peptides altered A beta aggregation kinetics and only two, KLVFF and KLVF, had any protective effect against A beta toxicity. The hybrid peptide KLVFF-KKKKKK dramatically altered A beta aggregation kinetics and aggregate morphology and provided significantly improved protection against A beta toxicity compared to the recognition peptide alone. In contrast, FAEDVG-KKKKKK possessed only modest inhibitory activity and had no marked effect on A beta aggregation. The scrambled sequence VLFKF was nearly as effective a recognition domain as KLVFF, suggesting the hydrophobic characteristics of the recognition sequence are critical. None of the cytoprotective peptides prevented A beta aggregation; rather, they increased aggregate size and altered aggregate morphology. These results suggest that coupling recognition with disrupting elements is an effective generalizable strategy for the creation of A beta inhibitors. Significantly, prevention of A beta aggregation may not be required fur prevention of toxicity.