Ferulic acid destabilizes preformed β-amyloid fibrils in vitro

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Abstract

Inhibition of the formation of β-amyloid fibrils (fAβ), as well as the destabilization of preformed fAβ in the CNS, would be attractive therapeutic targets for the treatment of Alzheimer’s disease (AD). We reported previously that curcumin (Cur) inhibits fAβ formation from Aβ and destabilizes preformed fAβ in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of ferulic acid (FA) on the formation, extension, and destabilization of fAβ at pH 7.5 at 37 °C in vitro. We next compared the anti-amyloidogenic activities of FA with Cur, rifampicin, and tetracycline. Ferulic acid dose-dependently inhibited fAβ formation from amyloid β-peptide, as well as their extension. Moreover, it destabilized preformed fAβs. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.

Section snippets

Materials and methods

Preparation of Aβ and fAβ solutions. Aβ(1–40) (a trifluoroacetate salt, Peptide Institute, Osaka, Japan) and Aβ(1–42) (a trifluoroacetate salt, Peptide Institute) were dissolved by brief vortexing in a 0.02% ammonia solution at a concentration of 500 μM (2.2 mg/mL) and 250 μM, respectively, in a 4 °C room and stored at −80 °C before assaying (fresh Aβ(1–40) and Aβ(1–42) solutions). fAβ(1–40) and fAβ(1–42) were formed from the fresh Aβ(1–40) and Aβ(1–42) solutions, respectively, sonicated, and stored

Results and discussion

As shown in Figs. 2A and B, when fresh Aβ(1–40) or Aβ(1–42) was incubated at 37 °C, the fluorescence of ThT followed a characteristic sigmoidal curve. This curve is consistent with a nucleation-dependent polymerization model [10]. When Aβ(1–40) was incubated with 10 and 50 μM FA, the final equilibrium level decreased dose-dependently (Fig. 2A). A similar effect of FA was observed with Aβ(1–42) (Fig. 2B). As shown in Figs. 2C and D, when fresh Aβ(1–40) or Aβ(1–42) was incubated with fAβ(1–40) or

Acknowledgments

The authors thank Drs. Souichi Okino and Kazuo Iwasa (Kanazawa University) for cooperation in the experiments. This work was supported in part by a Grant-in-Aid for Scientific Research (M.Y.), a grant for the 21st Century COE Program (on Innovative Brain Science for Development, Learning and Memory) (M.Y.), a grant for the Knowledge Cluster Initiative [High-Tech Sensing and Knowledge Handling Technology (Brain Technology)] (M.Y.), and a grant to the Amyloidosis Research Committee from the

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