ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Inhibition of the accumulation of amyloid β-peptide (Aβ) and the formation of β-amyloid fibrils (fAβ) from Aβ, as well as the degradation of pre-formed fAβ in the CNS would be attractive therapeutic objectives for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) inhibited fAβ formation from Aβ(1–40) and Aβ(1–42) dose-dependently in the range of 10–30 µmin vitro. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that NDGA dose-dependently breaks down fAβ(1–40) and fAβ(1–42) within a few hours at pH 7.5 at 37°C. At 4 h, the fluorescence of fAβ(1–40) and fAβ(1–42) incubated with 50 µm NDGA was 5% and 10% of the initial fluorescence, respectively. The activity of NDGA to break down these fAβs was observed even at a low concentration of 0.1 µm. At 1 h, many short, sheared fibrils were observed in the mixture incubated with 50 µm 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 fAβ(1–40) and fAβ(1–42), with other molecules reported to inhibit fAβ formation from Aβ and/or to degrade pre-formed fAβ both in vivo and in vitro. At a concentration of 50 µm, 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 〉 β-sheet breaker peptide (iAβ5). In cell culture experiments, fAβ disrupted by NDGA were less toxic than intact fAβ, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAβ formation from Aβ, as well as breaking down pre-formed fAβin vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2002.00904.x
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