Nordihydroguaiaretic acid does not disaggregate β-amyloid(1-40) protofibrils but does inhibit growth arising from direct protofibril association

Melissa A. Moss, Nicholas H. Varvel, Michael R. Nichols, Dana Kim Reed, Terrone L. Rosenberry

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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 β-protein (Aβ) fibrils. They concluded that NDGA could disaggregate Aβ 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 Aβ(1-40) fibrils and extended this observation to Aβ(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 Aβ 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 Aβ protofibrils were added to the incubation. Although NDGA failed to disaggregate Aβ 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 Aβ protofibrils. In addition, the binding of NDGA to Aβ 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.

Original languageEnglish (US)
Pages (from-to)592-600
Number of pages9
JournalMolecular pharmacology
Volume66
Issue number3
StatePublished - Sep 1 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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