title: Dihydroxybenzoic acid isomers differentially dissociate soluble biotinyl-Aβ(1-42) oligomers.
abstract: Polyphenolic compounds including a number of natural products such as resveratrol, curcumin, catechin derivatives, and nordihydroguaiaretic acid have effects on the assembly of Aβ fibrils and oligomers as well as on fibril morphology. Based on a lead structure obtained from a screen of a small molecule diversity library, simple benzoic acid derivatives distinguished by the number and position of hydroxyls on the aromatic ring displayed different abilities to dissociate preformed biotinyl-Aβ(1-42) oligomers. The 2,3-, 2,5-, and 3,4-dihydroxybenzoic acid (DHBA) isomers were active oligomer dissociators. The remaining DHBA isomers and the monohydroxy and unsubstituted benzoic acids were inactive and did not compete with the active compounds to block oligomer dissociation. None of the compounds blocked oligomer assembly, indicating that they do not interact with monomeric Aβ to shift the oligomer-monomer equilibrium. Dissociating activity was not associated with quinone redox cycling capacity of the compounds. Gallic acid (3,4,5-trihydroxybenzoic acid) stabilized biotinyl-Aβ(1-42) oligomers against intrinsic dissociation and blocked the effects of the active dissociators, independent of the concentration of dissociator. A model for the mechanism of action of the DHBA dissociators proposes that these compounds destabilize oligomer structure promoting progressive monomer dissociation rather than fissioning oligomers into smaller, but still macromolecular, species. Gallic acid blocks dissociation by stabilizing oligomers against this process.
authors: Department of Cellular and Molecular Biochemistry, Center on Aging, Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40506, United States. hlevine@email.uky.edu
authors: Harry
authors: H
authors: LeVine
authors: Levi
authors: L
authors: Lampe
authors: Lina
authors: L
authors: Abdelmoti
authors: Corinne E
authors: CE
authors: Augelli-Szafran
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D019817:Benzoic Acid / Q000737:chemistry*; D019921:Biotinylation; D002396:Catechols / Q000737:chemistry*; D004298:Dopamine / Q000031:analogs & derivatives / Q000737:chemistry; D005976:Glutaral / Q000737:chemistry; D006801:Humans; D062385:Hydroxybenzoates; D007536:Isomerism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D059748:Proteolysis; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D002396:Catechols; D062385:Hydroxybenzoates; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C022133:3,4-dihydroxybenzylamine; C009135:2,3-dihydroxybenzoic acid; D019817:Benzoic Acid; D005976:Glutaral; D004298:Dopamine