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.