Tau (7) is a major constituent of paired helical fila- ments (PHF) found in Alzheimer’s disease. The current study examines the possibility that the distinct prop- erties of PHF-associated T proteins (T~HF) result from post-translational modifications of normal soluble T ( T ~ ) . Following hydrofluoric acid (HF) treatment, TPHF proteins are heat- and acid-stable, soluble in 24N-morpho1ino)ethanesulfonic acid buffers and display the same molecular weight, PI, and immunochemical properties as normal 7.. Alkaline phosphatase treatment of dissociated PHF results in similar, although less extensive, electrophoretic changes and a reduction in PHF-1 immunoreactivity. Therefore, phosphorylation of normal T. appears to be responsible for the distinct properties of T~HF. Although our results suggest that all of the normal T isoforms are in PHF, the relative abun- dance of individual T species differs in HF-treated PHF and T. samples. Moreover, the loss of PHF following HF treatment suggests that post-translational modifications contribute to the structural stability of PHF.