title: Protective effects of caffeoylquinic acids on the aggregation and neurotoxicity of the 42-residue amyloid β-protein.
abstract: Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of 42-mer amyloid β-protein (Aβ42). Aβ42 aggregates through β-sheet formation and induces cytotoxicity against neuronal cells. Aβ42 oligomer, an intermediate of the aggregates, causes memory loss and synaptotoxicity in AD. Inhibition of Aβ42 aggregation by small molecules is thus a promising strategy for the treatment of AD. Caffeoylquinic acid (CQA), a phenylpropanoid found widely in natural sources including foods, shows various biological activities such as anti-oxidative ability. Previously, our group reported that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) rescued the cognitive impairment in senescence-accelerated-prone mice 8. However, structure-activity relationship of CQA derivatives on the aggregation and neurotoxicity of Aβ42 remains elusive. To evaluate the anti-amyloidogenic property of CQA-related compounds for AD therapy, we examined the effect of CQA and its derivatives on the aggregation and neurotoxicity of Aβ42. In particular, 4,5-di-O-caffeoylquinic acid (4,5-di-CQA) and 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri-CQA) strongly inhibited the aggregation of Aβ42 in a dose-dependent manner. Structure-activity relationship studies suggested that the caffeoyl group in CQA is essential for the inhibitory activity. These CQAs also suppressed the transformation into β-sheet and cytotoxicity against human neuroblastoma cells of Aβ42. Furthermore, 3,4,5-tri-CQA blocked the formation of Aβ42 oligomer. These results indicate that 3,4,5-tri-CQA could be a potential agent for the prevention of AD.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Miyamae
authors.forename: Manami
authors.initials: M
authors.lastname: Kurisu
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.forename: Junkyu
authors.initials: J
authors.lastname: Han
authors.forename: Hiroko
authors.initials: H
authors.lastname: Isoda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shigemori
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C538897:amyloid beta-protein (40-42); C472707:caffeoylquinic acid; D011801:Quinic Acid