Tau from Alzheimer’s disease (AD) paired helical filaments (PHF-tau) is phosphorylated at sites not found in autopsy-derived adult tau from normal human brains, and this suggested that PHF-tau is abnormally phosphorylated. To explore this hypothesis, we examined human adult tau from brain biopsies and demonstrated that biopsy-derived tau is phosphorylated at most sites thought to be abnormally phosphorylated in PHF-tau. These sites also were phosphorylated in autopsy-derived human fetal tau and rapidly processed rat tau. The hypophosphorylation of autopsy-derived adult human tau is due to rapid dephosphorylation postmortem, and protein phosphatases 2A (PPZA) and 2B (PPZB) in human brain biopsies dephosphorylate tau in a site-specific manner. The down-regulation of phosphatases (ie, PPZA and PPZB) in the AD brain could lead to the generation of maximally phosphorylated PHF-tau that does not bind microtubules and aggregates as PHFs in neurofibrillary tangles and dystrophic neurites. introduction

Paired helical filaments (PHFs) are composed of CNS tau proteins (designated PHF-tau or A68), and these abnormal filaments form the principal fibrous components in neurofibrillarytangles(NFTs), a major neuropathological lesion found in the brains of Alzheimer’s disease (AD) patients (Lee et al., 1991; Kosik, 1992; Lee and Trojanowski, 1992; Goedert, 1993; Trojanowski et al., 1993a, 1993b). Indeed, NFTs appear to correlate better with the severity and duration of AD than amyloid plaques (Dickson et al., 1991; Arriagada et al., 1992). The cloning and sequencing of the tau gene demonstrates that a total of six different tau isoforms can be generated from a single tau gene by alternative splicing (Goedert et al., 1989; Himmler, 1989). The ex-