title: Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer's beta-amyloid fibrils in vitro.
abstract: Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the degradation of pre-formed fAbeta in the CNS would be attractive therapeutic objectives for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42) dose-dependently in the range of 10-30 micromin vitro. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that NDGA dose-dependently breaks down fAbeta(1-40) and fAbeta(1-42) within a few hours at pH 7.5 at 37 degrees C. At 4 h, the fluorescence of fAbeta(1-40) and fAbeta(1-42) incubated with 50 microm NDGA was 5% and 10% of the initial fluorescence, respectively. The activity of NDGA to break down these fAbetas was observed even at a low concentration of 0.1 microm. At 1 h, many short, sheared fibrils were observed in the mixture incubated with 50 microm NDGA, and at 4 h, the number of fibrils reduced markedly, and small amorphous aggregates were observed. We next compared the activity of NDGA to break down fAbeta(1-40) and fAbeta(1-42), with other molecules reported to inhibit fAbeta formation from Abeta and/or to degrade pre-formed fAbeta both in vivo and in vitro. At a concentration of 50 microm, the overall activity of the molecules examined in this study was in the order of: NDGA >> rifampicin = tetracycline > poly(vinylsulfonic acid, sodium salt) = 1,3-propanedisulfonic acid, disodium salt > beta-sheet breaker peptide (iAbeta5). In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.
authors.affiliation: Department of Pathology, Fukui Medical University, Fukui, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshiike
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D052160:Benzothiazoles; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D046911:Macromolecular Substances; D009637:Masoprocol / Q000737:chemistry* / Q000494:pharmacology; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D046911:Macromolecular Substances; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D009637:Masoprocol