Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations

Several recent studies support a link between τ protein phosphorylation and adduction of τ by reactive carbonyls. Indeed, the phosphorylation- dependent adduction of τ by carbonyl products resulting from lipid peroxidation creates the neurofibrillary tangle-related antigen, Alz50. To determine whether epitopes of carbonyl-modified τ are major conformational changes associated with neurofibrillary tangle formation, we examined seven distinct antibodies raised against neurofibrillary tangles that recognize unique epitopes of τ in Alzheimer disease. Consistently, all seven antibodies recognize τ more strongly (4- to 34-fold) after treatment of normal τ with the reactive carbonyl, 4-hydroxy-2-nonenal (HNE), but only when τ is in the phosphorylated state. These findings not only support the idea that oxidative stress is involved in neurofibrillary tangle formation occurring in brains of Alzheimer disease patients, but also show, for the first time, that HNE modifications of τ promote and contribute to the generation of the major conformational properties defining neurofibrillary tangles.