Neuronal
protein inclusions are a common feature in
Alzheimer disease (AD) and
Pick disease. Even though the inclusions are morphologically different, flame-shape structure for AD vs. spherical structure for
Pick disease, both have filaments mainly composed of
tau protein. In AD, a well-defined pattern of conformational changes and truncation has been described. In this study, we used
laser scanning confocal microscopy to characterize and compare the processing of
tau protein during
Pick disease with that found in AD. We found that
tau protein of
Pick disease preserves most of the relevant
epitopes found in AD, the conformational foldings labelled by Alz-50 and
Tau-66, the cleavage sites D(421) and E(391), as well as many phosphorylated sites, such as Ser(199/202), Thr(205) and Ser(396/404). We found a strong pattern of association between phosphorylation and cleavage at site D(421), as well as the phosphorylation and the conformational Alz-50
epitope. When we used late AD markers such as the conformational
Tau-66 epitope and MN423 (cleavage at site E(391)) in Pick bodies (PBs), the overlap was significantly less. Furthermore, following morphological quantification, we found significantly higher numbers of phosphorylated tau in PBs. Overall, our findings suggest that phosphorylation is an early event, likely preceding the cleavage of tau at D(421). Despite this consistency with AD, we found a major distinction, namely that PBs lack beta-sheet conformation. We propose a scheme of early tau processing in these structures, similar to neurofibrillary tangles of AD.