Oxidative regulation of fatty acid-induced tau polymerization

Alzheimer's disease (AD) is characterized by the presence of amyloid-positi ve senile plaques and tau-positive neurofibrillary tangles. Aside from thes e two pathological hallmarks, a growing body of evidence indicates that the amount of oxidative alteration of vulnerable molecules such as proteins, D NA, and fatty acids is elevated in the brains of AD patients. It has been h ypothesized that the elevated amounts of protein oxidation could lead direc tly to the formation of neurofibrillary tangles through a cysteine-dependen t mechanism. We have tested this hypothesis in an in vitro system in which tau assembly is induced by fatty acids. Using sulfhydryl protective agents and site-directed mutagenesis, we found that cysteine-dependent oxidation o f the tau molecule is not required for its polymerization and may even be i nhibitory. However, by adjusting the oxidative environment of the polymeriz ation reaction through the addition of a strong antioxidant or through the addition of an oxidizing system consisting of iron, adenosine diphosphate, and ascorbate, we found that oxidation does play a major role in our in vit ro paradigm. The results indicated that fatty acid oxidation, the amount of which is found to be elevated in AD patients, can facilitate: the polymeri zation of tau. However, "overoxidation" of the fatty acids can inhibit the process. Therefore, we postulate that specific fatty acid oxidative product s could provide a direct link between oxidative stress mechanisms and the f ormation of neurofibrillary tangles in AD.