Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly.

Abstract

The link between many neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and the aberrant folding and aggregation of proteins has prompted a comprehensive search for small organic molecules that have the potential to inhibit such processes. Although many compounds have been reported to affect the formation of amyloid fibrils and/or other types of protein aggregates, the mechanisms by which they act are not well understood. A large number of compounds appear to act in a nonspecific way affecting several different amyloidogenic proteins. We describe here a detailed study of the mechanism of action of one representative compound, lacmoid, in the context of the inhibition of the aggregation of the amyloid β-peptide (Aβ) associated with Alzheimer's disease. We show that lacmoid binds Aβ(1-40) in a surfactant-like manner and counteracts the formation of all types of Aβ(1-40) and Aβ(1-42) aggregates. On the basis of these and previous findings, we are able to rationalize the molecular mechanisms of action of nonspecific modulators of protein self-assembly in terms of hydrophobic attraction and the conformational preferences of the polypeptide.

• Authors: Axel Abelein, Benedetta Bolognesi, Christopher M Dobson, Astrid Gräslund, Christofer Lendel
• Journal: Biochemistry (Biochemistry) Vol. 51 Issue 1 Pg. 126-37 (Jan 10 2012) ISSN: 1520-4995 [Electronic] United States
• PMID: 22133042 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Oxazines
• Peptide Fragments
• Small Molecule Libraries
• Surface-Active Agents
• amyloid beta-protein (1-40)
• lacmoid
• Congo Red

Topics

• Amyloid beta-Peptides (antagonists & inhibitors, biosynthesis, chemistry)
• Binding, Competitive
• Circular Dichroism
• Congo Red (chemistry)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Models, Molecular
• Nanostructures (chemistry)
• Nuclear Magnetic Resonance, Biomolecular
• Oxazines (chemistry)
• Peptide Fragments (antagonists & inhibitors, biosynthesis, chemistry)
• Protein Binding
• Protein Conformation
• Scattering, Radiation
• Small Molecule Libraries (chemistry)
• Surface-Active Agents (chemistry)