Recognition Sequence Design for Peptidyl Modulators of β-Amyloid Aggregation and Toxicity

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Abstract
β-Amyloid (Aβ), 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 Aβ toxicity, based on linking a recognition element for Aβ to a disrupting element designed to interfere with Aβ aggregation. One such compound, with the 15−25 sequence of Aβ as the recognition element and a lysine hexamer as the disrupting element, altered Aβ aggregation kinetics and protected cells from Aβ 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 Aβ aggregation kinetics and only two, KLVFF and KLVF, had any protective effect against Aβ toxicity. The hybrid peptide KLVFF-KKKKKK dramatically altered Aβ aggregation kinetics and aggregate morphology and provided significantly improved protection against Aβ toxicity compared to the recognition peptide alone. In contrast, FAEDVG-KKKKKK possessed only modest inhibitory activity and had no marked effect on Aβ 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 Aβ 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 Aβ inhibitors. Significantly, prevention of Aβ aggregation may not be required for prevention of toxicity.