Pick bodies and ballooned cells of Pick's disease and the neurofibrillary lesions of Alzheimer's disease are characterized by the presence of hyperphosphorylated microtubule-associated protein tau. Little is known about the mechanisms underlying tau hyperphosphorylation in Pick's disease and the distribution of abnormal tau in affected neurons. We have used a panel of phosphorylation-dependent (AT270, AT8, AT180, 12E8, PHF-1, AT10 and Tau-1) and phosphorylation-independent anti-tau antibodies (N-tau 5 and 134) to stain brain tissue sections from subjects with Pick's disease and Alzheimer's disease. These antibodies labeled Pick bodies and neurofibrillary lesions in a similar way, with the exception of antibody 12E8, which stained a subset of neurofibrillary tangles, but no Pick bodies. Moreover, abundant AT8- and PHF-1-positive neuritic profiles were observed in cortical areas rich in Pick bodies, even in the complete absence of neurofibrillary lesions. Unlike the Gallyas-positive neuropil threads of Alzheimer's disease, which were of variable diameter and covered by spiny appendages, neuritic profiles of Pick's disease showed a regular diameter, appeared smooth and were Gallyas-negative. In contrast to Alzheimer's disease, dendritic branches of neurons containing Pick bodies were not labeled by anti-tau antibodies. In the hippocampus, numerous tau-positive axon terminals were found along dendrites of the polymorphic layer of the dentate gyrus. Our results indicate that tau proteins in Pick's disease and Alzheimer's disease share similar phosphorylated residues, with the exception of serine 262, which is phosphorylated in Alzheimer tangles but not in Pick bodies or neuritic profiles. Furthermore, we show that hyperphosphorylated tau segregates to different neuronal compartments in the two diseases, with a somatoaxonal distribution in Pick's disease and a somatodendritic distribution in Alzheimer's disease.