Apolipoprotein E and Antioxidants Have Different Mechanisms of Inhibiting Alzheimer's β-Amyloid Fibril Formation in Vitro

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Abstract
We compared the mechanisms of apolipoprotein E- (apoE-) and antioxidant- (AO-) mediated inhibition of β-amyloid fibril (fAβ) formation in vitro, based on a nucleation-dependent polymerization model using fluorescence spectroscopy with thioflavin T. We first applied a kinetic plot to transform a sigmoidal time-course curve of fAβ formation from freshly prepared amyloid β-peptides (Aβ) into a straight line. Mathematical treatment of this plot demonstrated that the above-described sigmoidal curve is a logistic curve and provided us with a kinetic parameter t1/2, the time when the rate of fAβ formation is maximum. t1/2 of β-amyloids (Aβ) (1−42) and (1−40) were 18.7 ± 1.7 min and 6.3 ± 0.2 h, respectively (mean ± SD, n = 3) and were independent of the initial Aβ concentration examined. Although apoE extended t1/2 of both Aβs in a dose-dependent manner, AO did not. On the other hand, the final amount of fAβ formed was decreased by both apoE and AO dose-dependently. We then analyzed the effect of apoE and AO on the extension reaction of fAβ, based on a first-order kinetic model. Although apoE extended the time to proceed to equilibrium in a dose-dependent manner, AO did not. On the other hand, both apoE and AO dose-dependently decreased the final amount of fAβ formed. These results indicate that apoE and AO inhibit fAβ formation in vitro by different mechanisms and suggest the existence of multiple pharmacological targets for the prevention of fAβ formation.