[Search for antiamyloidogenic compounds based on a nucleation-dependent polymerization model].
We have proposed that a nucleation-dependent polymerization model could explain the general mechanisms of amyloid fibril formation in vitro. Based on this model, we systematically demonstrated that several classes of organic compounds (e.g., wine-related polyphenols, non-steroidal anti-inflammatory drugs) not only inhibit the formation of Abeta amyloid fibrils from Abeta and their extension, but also destabilize Abeta amyloid fibrils dose-dependently in vitro. We found significant positive correlations of the effective concentrations (EC(50)) of these compounds ranging from 10 nM to 10 microM, for the formation and destabilization of Abeta amyloid fibrils. We next investigated the anti-amyloidogenic effects of five flavonoids on Abeta amyloid fibrils in vitro. Oxidized flavonoids generally inhibited fibril formation significantly more potently than fresh compounds. By surface plasmon resonance (SPR) analysis, distinct association and dissociation reactions of myricetin (Myr) to Abeta amyloid fibrils were observed, in contrast to the very weak binding to the Abeta monomer. A significant decrease in the rate of fibril extension was observed when>0.5 microM of Myr was injected into the SPR experimental system. These findings suggest that flavonoids, especially Myr exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fibrils, rather than to Abeta monomers. This working model should prove useful not only for the rational development of preventive and therapeutics for Alzheimer's disease and other human amyloidosis, but also for understanding the basic mode of action of amyloid imaging compounds.
Naiki
Hironobu
H
Department of Pathological Sciences, University of Fukui, Fukui, Japan. naiki@u-fukui.ac.jp
Hasegawa
Kazuhiro
K
Ono
Kenjiro
K
Yamada
Masahito
M
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D011108:Polymers; D059808:Polyphenols; D014920:Wine
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D059808:Polyphenols