Phenolic Compounds Prevent Amyloid β-Protein Oligomerization and Synaptic Dysfunction by Site-specific Binding

• Published in: The Journal of biological chemistry 2012-04, Vol.287 (18), p.14631-14643
• Main Authors: Ono, Kenjiro, Li, Lei, Takamura, Yusaku, Yoshiike, Yuji, Zhu, Lijun, Han, Fang, Mao, Xian, Ikeda, Tokuhei, Takasaki, Jun-ichi, Nishijo, Hisao, Takashima, Akihiko, Teplow, David B., Zagorski, Michael G., Yamada, Masahito
• Format: Article
• Language: English
• Subjects: Aggregation; Alzheimer Disease; Amyloid; Amyloid Beta Protein; Amyloid beta-Peptides - metabolism; Animals; Antioxidants - pharmacology; Cinnamates - pharmacology; Depsides - pharmacology; Flavonoids - pharmacology; HEK293 Cells; Humans; Mice; Molecular Bases of Disease; Oligomer; Phenolic Compounds; Polyphenols; Protein Multimerization - drug effects; Rosmarinic Acid; Synapses; Synapses - metabolism; Synapses - pathology; Synaptic Toxicity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.325456

Cerebral deposition of amyloid β protein (Aβ) is an invariant feature of Alzheimer disease (AD), and epidemiological evidence suggests that moderate consumption of foods enriched with phenolic compounds reduce the incidence of AD. We reported previously that the phenolic compounds myricetin (Myr) and rosmarinic acid (RA) inhibited Aβ aggregation in vitro and in vivo. To elucidate a mechanistic basis for these results, we analyzed the effects of five phenolic compounds in the Aβ aggregation process and in oligomer-induced synaptic toxicities. We now report that the phenolic compounds blocked Aβ oligomerization, and Myr promoted significant NMR chemical shift changes of monomeric Aβ. Both Myr and RA reduced cellular toxicity and synaptic dysfunction of the Aβ oligomers. These results suggest that Myr and RA may play key roles in blocking the toxicity and early assembly processes associated with Aβ through different binding. Background: Epidemiological evidence suggests that consumption of phenolic compounds reduce the incidence of Alzheimer disease (AD). Results: Myricetin and rosmarinic acid reduced cellular and synaptic toxicities by inhibition of amyloid β-protein (Aβ) oligomerization. Myricetin promoted NMR changes of Aβ. Conclusion: Phenolic compounds are worthy therapeutic candidates for AD. Significance: Phenolic compounds blocked early assembly processes of Aβ through differently binding.