Nordihydroguaiaretic acid does not disaggregate beta-amyloid(1-40) protofibrils but does inhibit growth arising from direct protofibril association.
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 beta-protein (Abeta) fibrils. They concluded that NDGA could disaggregate Abeta 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 Abeta(1-40) fibrils and extended this observation to Abeta(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 Abeta 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 Abeta protofibrils were added to the incubation. Although NDGA failed to disaggregate Abeta 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 Abeta protofibrils. In addition, the binding of NDGA to Abeta 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.
Department of Neurosciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Melissa A
MA
Moss
Nicholas H
NH
Varvel
Michael R
MR
Nichols
Dana Kim
DK
Reed
Terrone L
TL
Rosenberry
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology*; D052160:Benzothiazoles; D005453:Fluorescence; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; D009637:Masoprocol