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Nordihydroguaiaretic Acid Does Not Disaggregate -Amyloid(1–40) Protofibrils but Does Inhibit Growth Arising from Direct Protofibril Association

Department of Neurosciences, Mayo Clinic, Jacksonville, Florida

Nordihydroguaiaretic acid (NDGA) was observed by Ono et al. (J Neurochem 87:172–181, 2002) to decrease the fluorescence of thioflavin T associated with freshly extended amyloid -protein (A) fibrils. They concluded that NDGA could disaggregate A fibrils into aggregates that were larger than monomers or oligomers and did not bind thioflavin T. Such an effect could be of therapeutic importance in the treatment of Alzheimer's disease. In the current study, we confirmed that NDGA induces a decrease in the fluorescence of thioflavin T associated with A(1–40) fibrils and extended this observation to A(1–40) protofibrils. However, attempts to identify protofibril disaggregation products using dynamic light scattering, electron microscopy, and size exclusion chromatography failed to demonstrate any decrease in aggregate size or concentration or a parallel increase in A monomers or small oligomers when protofibrils were incubated with excess NDGA. We propose instead that the decreases in thioflavin T fluorescence resulted from either displacement or conformational alteration of thioflavin T upon the binding of NDGA to these aggregates. In fact, the same equilibrium fluorescence values were observed regardless of the order in which NDGA, thioflavin T, and A protofibrils were added to the incubation. Although NDGA failed to disaggregate A protofibrils, it did inhibit direct protofibril-protofibril association but did not alter protofibril elongation by monomer addition. These results suggest that NDGA might bind along the lateral surface of A protofibrils. In addition, the binding of NDGA to A protofibrils increased their nonspecific adherence to Superdex 75 resin and diminished their effects on cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

Address correspondence to: Terrone L. Rosenberry, Department of Neurosciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail address: rosenberry{at}mayo.edu

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