Phage display affords peptides that modulate beta-amyloid aggregation

J Am Chem Soc. 2006 Sep 13;128(36):11882-9. doi: 10.1021/ja0619861.

Abstract

As the population ages, the need to develop methods to understand and intercept the processes responsible for protein aggregation diseases is becoming more urgent. The aggregation of the protein beta-amyloid (Abeta) has been implicated in Alzheimer's Disease (AD); however, whether the toxic species is a large, insoluble aggregate or some lower order form is not yet known. Agents that can modulate the aggregation state of Abeta could resolve this controversy by facilitating our understanding of the consequences of aggregation and its underlying mechanism. To date, however, ligands that bind to specific forms of Abeta have not been identified. To address this deficiency, we tested whether phage display could yield such ligands by screening libraries against Abeta in two different states: monomeric or highly aggregated. Intriguingly, the peptides selected had different effects on Abeta aggregation. Peptides selected for binding to monomeric Abeta did not perturb aggregation, but those selected using highly aggregated Abeta increase the rate of aggregation drastically. The latter also alter the morphology of the resulting aggregate. The ability of a peptide to promote aggregation correlated with its affinity for the N-terminal 10 residues of Abeta. This result indicates that the mechanism by which the peptides influence aggregation is related to their affinity for the Abeta N-terminus. Thus, the identification of compounds that bind to this Abeta section can afford agents that affect aggregation. Moreover, the data suggest that endogenous ligands that interact with the N-terminal region can influence the propensity of Abeta to form aggregates and the morphology of those that form. Our data highlight the utility of phage display for identifying ligands that bind to target proteins in different states, and they indicate that such agents can be used to perturb protein aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Bacteriophage M13 / genetics*
  • Benzothiazoles
  • Light
  • Microscopy, Electron
  • Molecular Sequence Data
  • Peptide Library*
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Scattering, Radiation
  • Thiazoles / chemistry
  • Thiazoles / metabolism

Substances

  • Amyloid beta-Peptides
  • Benzothiazoles
  • Peptide Library
  • Peptides
  • Thiazoles
  • thioflavin T