Inhibition of the formation of P-amyloid fibrils (fA beta), as well as the destabilization of preformed fA beta in the CNS would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of alpha-lipoic acid (LA) and the metabolic product of LA, dihydrolipoic acid (DHLA), on the formation, extension, and destabilization of fA beta at pH 7.5 at 37 degrees C in vitro. LA and DHLA dose-dependently inhibited fA beta formation from amyloid P-protein, as well as their extension. Moreover, they destabilized preformed fA beta s. LA and DHLA could be key molecules for the development of therapeutics for AD. (c) 2006 Elsevier Inc. All rights reserved.