SEQUENTIAL-CHANGES OF TAU-SITE-SPECIFIC PHOSPHORYLATION DURING DEVELOPMENT OF PAIRED HELICAL FILAMENTS

It has been reported that many tau sites in neurofibrillary tangles (N FT) are abnormally phosphorylated. We investigated the phosphorylation of tau in the hippocampus of nondemented patients and Alzheimer's dis ease patients by immunostaining with five site-specific antibodies aga inst phosphorylated tau. In the pretangle stage, tau in neuropil threa ds was phosphorylated at serines 199, 202 and 409, numbered according to the longest human tau isoform, whereas tau in some neuronal soma wa s phosphorylated at serines 199, 202, 409 and 422. Tau at the stage of NFT was phosphorylated at serine 396 and threonine 231 in addition to serines 199, 202, 409 and 422. In the advanced stage, tau in ghost ta ngles was phosphorylated mainly at serine 396. These results suggest t hat the phosphorylation of each site in tau differs among the maturing stages of neurofibrillary change and that abnormal phosphorylation of tau in the neuronal soma occurs at 199, 202, 409 and 422 earlier than at threonine 231 and serine 395.